A Greek family with a follicular variant of familial papillary thyroid carcinoma: TCO, MNG1, fPTC/PRN, and NMTC1 excluded as susceptibility loci.

The familial form of nonmedullary thyroid carcinoma (FNMTC) has been recognized as a distinct clinical entity and is characterized by multifocality and a more severe phenotype than its sporadic counterpart. The majority of FNMTC pedigrees are small in size, show variable modes of inheritance, and may present with a variety of additional benign thyroid disorders. The existence of marked phenotypic differences between FNMTC families suggests that there is genetic heterogeneity. Recent studies have mapped a susceptibility locus for FNMTC at 2q21. This locus appears particular relevant to families with at least one case of the follicular variant of papillary thyroid cancer (fvPTC). We describe the clinical and pathologic characteristics of a large three-generation fPTC kindred, with two of the four PTC patients presented with the follicular variant of PTC. It is of interest the occurrence of PTC in three siblings within a period of 3 years. In addition, multinodular goiter (MNG) was diagnosed in seven individuals, lymphocytic thyroiditis in four, while one diagnosed with a benign adenoma. From the PTC patients, one had MNG and fvPTC, one MNG, lymphocytic thyroiditis and papillary pattern of PTC, one lymphocytic thyroiditis and fvPTC, and one MNG and papillary pattern of PTC. The inheritance pattern was autosomal dominant with incomplete penetrance and women were affected more frequently than men. Considering all PTC-affected individuals, the limit of detection (LOD) score we got for this family on 2q21 was 0.5. The low LOD score is caused by a PTC patient who does not share the affected haplotype, suggesting that maybe a new locus for PTC predisposition is present in this kindred. Linkage analysis also excluded TCO, MNG, and fPTC/PRN as susceptibility loci to FNMTC in this family.     

Familial non-medullary thyroid carcinoma: pathology review in 27 affected cases from 13 French families

BACKGROUND AND OBJECTIVES: When familial non-medullary thyroid cancer (FNMTC) develops with no obvious associated pathogenetic factor, an inherited predisposition may underlie the process. The present study was conducted because detailed pathological findings are lacking in most series of FNMTC. PATIENTS AND METHODS: Thirteen families comprising 27 cases of FNMTC were included (1.8% of differentiated thyroid carcinoma). The family relationship (20 F, 7 M; age 46 +/- 16 years; mean +/- SD) was 'siblings' in eight families, 'parent and child' in four and 'aunt and niece' in one. Careful pathological review of the thyroid tumours (papillary/follicular: 25/2, size: 16 +/- 11 mm) was performed. RESULTS: Initial staging according to extension was as follows: grade I (n = 16), II (n = 2), III (n = 6), IV (n = 3). Fourteen tumours were papillary microcarcinomas (size: 8 +/- 2 mm). No tumour phenotype that may be considered specific for FNMTC was found when considering either age, pathological findings or tumour aggressiveness. Although rare events were found in both relatives of some families suggesting a putative 'familial' phenotype of FNMTC, this may be fortuitous. CONCLUSION: Micro familial non-medullary thyroid cancers are more common than previously reported and further studies are required to be able to distinguish this subgroup from sporadic papillary microcarcinomas. The careful pathological review of the familial non-medullary thyroid cancer in this study does not seem to point to a distinct subgroup of familial differentiated thyroid carcinoma although the data are intriguing. Genetic studies are now required to investigate this issue.     

A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer

We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.     

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N- and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.     

Chromosomal aberrations by comparative genomic hybridization in thyroid tumors in patients with familial nonmedullary thyroid cancer.

PURPOSE: Nonmedullary thyroid cancer is the most common form of thyroid cancer and its familial form (FNMTC) is increasingly recognized as a distinct clinical entity. However, the genetic background of FNMTC is still poorly understood and the causative gene(s) have not yet been identified. METHODS: Because comparative genomic hybridization allows for screening of the entire tumor genome simultaneously for chromosomal gains and/or losses without prior knowledge of potential aberrations, we used this technique in thyroid normal and neoplastic samples from FNMTC patients (1) to analyze whether chromosomal aberrations would correlate with inheritance pattern, and/or clinicopathologic features and (2) to compare comparative genomic hybridization (CGH) findings in familial tumors with those already known in sporadic differentiated thyroid cancers. RESULTS: No common germline or somatic chromosomal aberrations were observed in patients with FNMTC because the frequencies and most locations of chromosomal aberrations in familial tumors were also common in sporadic tumors. However, some somatic aberrations were only found in familial tumors (gains in 2q, 3q, 18p, and 19p). Common aberrations in familial tumors corresponded to several locations of candidate genes already reported for sporadic thyroid tumorigenesis. CONCLUSIONS: Our findings suggest that chromosomal aberrations in thyroid tumors in patients with FNMTC are not related to inheritance pattern but rather to tumorigenesis.     

Prevalence and prognosis of familial follicular thyroid carcinoma

Although the responsible gene has not yet been identified, patients with differentiated thyroid carcinoma, including papillary and follicular carcinomas, demonstrating a family history have been reported and patients having one or more family members with differentiated carcinoma among their first-degree relatives are designated as having familial nonmedullary thyroid carcinoma (FNMTC). In this study, we investigated the biological characteristics, including prognosis, of familial follicular carcinoma. Three hundred and nineteen patients who underwent initial surgery for follicular thyroid carcinoma between 1987 and 2004 who were enrolled in this study. Of these 319 patients, 6 patients (1.9%) in 6 families were classified as having familial follicular carcinoma based on the criteria described above. The incidence of aggressive characteristics such as male gender, age 45 years or older, poor differentiation, widely invasive carcinoma, tumor larger than 4 cm and distant metastasis at diagnosis did not differ between familial and sporadic follicular carcinomas. One patient with familial follicular carcinoma underwent re-operation because of newly detected papillary carcinoma in the remnant thyroid 160 months after the initial surgery, but none of the 6 patients with familial carcinoma showed recurrence or died of follicular carcinoma. We can therefore conclude that FMNTC of the follicular type is very rare and there is no evidence that familial follicular carcinoma is more aggressive or has a worse prognosis than sporadic follicular carcinoma. The therapeutic strategy for follicular carcinoma might depend on conventional prognostic factors such as poor differentiation and distant metastasis at diagnosis, but not on whether the carcinoma is familial or sporadic.     

Disparities between male and female patients with thyroid cancers: sex difference or gender divide?

OBJECTIVE: This investigation was undertaken to quantify histopathological disparities between male and female patients with sporadic and hereditary thyroid cancers, which may reflect a biological 'sex difference' or a behavioural 'gender divide'. DESIGN: Retrospective cohort analysis (November 1994-January 2006). PATIENTS: 1298 Consecutive surgical patients with sporadic papillary (n = 587), sporadic follicular (n = 232), sporadic medullary (n = 320), and hereditary medullary thyroid cancers (n = 159) from a tertiary referral centre. MEASUREMENTS: Age at diagnosis of cancer, primary tumour diameter, frequency of extrathyroidal extension, lymph node and distant metastases, and cancer subtypes. RESULTS: Primary diameters of sporadic tumour entities (papillary, 26.0 vs. 19.3 mm; follicular, 54.9 vs. 35.1 mm; and medullary, 27.9 vs. 20.8 mm), but not hereditary medullary cancers, were significantly (P 相似文献   

Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma

Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain neurological and haematological disorders. This study was conducted to determine whether anticipation occurs in familial non-Hodgkin's lymphoma (NHL). Eleven published reports of multigenerational familial NHL were analysed for evidence of anticipation, together with 18 previously unreported families with familial NHL. Differences in disease-free survival between generations were determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. These analyses were also performed separately using only parent-child pairs with age of onset > 25 years to avoid ascertainment bias. In addition, the age at onset distribution of the studied cases was compared with that of the Surveillance Epidemiology and End Results (SEER) Program using data for 1973-98. The median ages at onset in the child and parent generations of all families (48.5 and 71.3 years respectively) and in the selected pairs (52.5 and 71.5 years respectively) were significantly different (P < 0.000002 and P < 0.000001 respectively). The null hypothesis was rejected for all (P < 0.000001) as well as selected pairs (P < 0.000003). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.009), but not between the parent generation and the SEER population. Anticipation occurs in familial NHL, which suggests a genetic basis for it.     

Genetic heterogeneity in familial nonmedullary thyroid carcinoma: exclusion of linkage to RET, MNG1, and TCO in 56 families. NMTC Consortium.

Epidemiological studies show a very high relative risk for first degree relatives of probands with thyroid cancer. The familial form of nonmedullary thyroid carcinoma (NMTC) gives a more severe phenotype and appears earlier than its sporadic counterpart. Moreover, benign thyroid pathologies are often observed in NMTC kindreds. Little is known about the genetic risk factors of the disease. To study them, an international consortium has been organized at the International Agency for Research on Cancer over the past 2 yr to collect biological samples from NMTC families. The only genes known to be directly involved in susceptibility to NMTC are MNG1 on chromosome 14q32 and TCO on chromosome 19q13.2, previously localized by us and others. In addition to those two genes, the genes for Cowden's syndrome and familial adenomatous polyposis are associated with thyroid cancer, but not as an indicative phenotype. Another important gene in thyroid carcinogenesis is RET, which is mutated in the majority of cases of hereditary medullary thyroid cancer and rearranged in an important fraction of sporadic cases of NMTC. Here we report the result of a linkage analysis performed on the 56 more informative kindreds we have collected through the international consortium. Linkage analysis using both parametric and nonparametric methods excluded MNG1, TCO, and RET as major genes of susceptibility to NMTC and demonstrated that this trait is characterized by genetic heterogeneity.     

Analysis of immune regulatory genes in familial and sporadic Graves' disease

Graves' disease (GD) is seen in apparently sporadic and familial forms. At least two immune regulatory genes are associated with GD, human leukocyte antigen (HLA) and cytotoxic T lymphocyte antigen-4 (CTLA-4). The aim of our study was to examine the contributions of HLA and CTLA-4 to the familial clustering of GD by analyzing them for association with familial and sporadic GD. We analyzed 160 Caucasian GD patients (69 familial and 91 sporadic), and 150 matched controls. Analysis of all GD patients demonstrated significant associations between GD and HLA-DR3 [P = 9.0 x 10(-7); relative risk (RR) = 3.8] and two CTLA-4 single nucleotide polymorphisms (SNPs), A/G(49) SNP (P = 0.03; RR = 1.5), and CT60 SNP (P = 0.03; RR = 1.4). Moreover, there was evidence for joint susceptibility to risk between HLA-DR3 and CTLA-4, giving a combined RR of 5.9. Subset analysis demonstrated no significant difference between the frequencies of HLA-DR3 and the susceptibility alleles of CTLA-4 A/G(49) and CT60 SNPs in the familial and sporadic GD subsets (P > 0.05). These results suggested that HLA-DR3 and CTLA-4 conferred a general increased risk for GD in both the sporadic and familial forms, and that the risk conferred by them was additive. However, HLA-DR3 and CTLA-4 did not have a stronger effect in the familial GD patients, suggesting that additional genes must contribute to the aggregation of GD within families.     

Frequency of NOD2/CARD15 variants in both sporadic and familial cases of Crohn''s disease across Italy. An Italian Group for Inflammatory Bowel Disease study

BACKGROUND: Three variants of the NOD2/CARD15 gene are strongly associated with susceptibility to Crohn's disease; however, striking racial and geographic differences of their frequency have been described. AIMS: We have compared the allele frequencies of familial cases of Crohn's disease recruited in a multicentre study across Italy, in order to disclose possible geographic heterogeneity. Moreover, we also compared the allele frequencies in sporadic cases of Crohn's disease and healthy controls from Southern Italy with those reported in other two populations from Central and Northern Italy. SUBJECTS AND METHODS: A total of 731 subjects were genotyped for the polymorphism of three main variants (R702W, G908R and 1007 fs): 152 patients were familial cases of Crohn's disease, 183 were healthy first-degree relatives, 180 were sporadic cases of Crohn's disease, and 216 were unrelated healthy subjects. RESULTS: The frequency of the frameshift mutation (1007 fs) was significantly higher in both familial and sporadic cases of Crohn's disease (P = 0.000001), and healthy first-degree relatives (P = 0.0001) compared to controls. At least one risk allele was found in 44% of familial Crohn's disease patients, compared to 7% of healthy controls (OR = 4; CI = 2-6.5). Two risk alleles were found in 14% of familial Crohn's disease, compared to less than 1% of controls (OR = 26: CI = 4-129). CONCLUSIONS: Our data confirm the strong correlation between the 1007 fs variant and Crohn's disease, in both familial and sporadic cases. Moreover, no significant difference of allele frequencies was detected in familial cases, sporadic cases and healthy controls among different geographic areas of Italy.     

Clinical characterization of familial isolated pituitary adenomas

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.     

Anticipation phenomenon in familial adenomatous polyposis:an analysis of its origin

AIM:To analyze the origin of the anticipation phenomenon, which means earlier death in successive generation in familial adenomatous polyposis.METHODS:The study subjects were 2161 patients with familial adenomatous polyposis and their 7465 first degree relatives who were members of 750 families registered at our Polyposis Registry. The ages at death and cumulative mortality rates in theparent, the proband, and the child generations were compared for both all subjects and the patients alone.RESULTS:In the patients over 5 years of age, the mean age at death was 50.9 years for the parent, 42.3 years for the proband, and 33.3 years for the child generations, respectively a(c)(P < 0.001). The deceased rates in the three generations were 90.7%, 51.3% and 23.1% of the patients, respectively, and this difference was the main cause of the anticipation measured by parent-child paring method. The cumulative mortality rates for all subjects failed to show anticipation, however the cumulative mortality rates for the patients showed the anticipation. The anticipation phenomenon was shown by any parent-child pairing methods for the deceased patients. Other important causes of the anticipation were different proportion of causes of death between generations a(c)(P <0.001), and a low proportion of detected or deceased patients (P < 0.001) in the child generation.CONCLUSION:Anticipation in familial adenomatous polyposis may be caused by parent child paring methods as well as several intergenerational biases.     

Anticipation in familial chronic lymphocytic leukaemia

Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain heritable neurological disorders and in multiple myeloma, non-Hodgkin's lymphoma and other haematological neoplasms. The present study was conducted to determine whether anticipation occurs in familial chronic lymphocytic leukaemia (CLL). Fourteen published reports of multigenerational familial CLL were analysed for anticipation, together with 10 previously unreported families with familial CLL, and the difference in disease-free survival between generations was determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. The age at onset of the studied cases was also compared with that of the Surveillance Epidemiology and End Results (SEER) Program of the U.S. National Cancer Institute. The median ages at onset in the child and parent generations of all families (51.0 and 72.0 years respectively) were significantly different (P < 0.000001), and the null hypothesis was rejected (P < 0.000001). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.00001), but not between the parent generation and the SEER population. Anticipation characterizes familial CLL.     

Juvenile systemic lupus erythematosus in multicase families from Saudi Arabia: comparison of clinical and laboratory variables with sporadic cases

The object of this study was to compare patients with familial versus sporadic systemic lupus erythematosus (SLE) with respect to clinical, laboratory variables and outcome. The familial SLE group comprised 12 patients while the comparative group comprised 24 patients selected by systemic sampling from our pediatric rheumatology clinic database. Those patients are listed according to the date of referral, which represents a sampling frame. The first patient was chosen randomly and subsequent patients were chosen at intervals of three. The two groups were compared with respect to: demographic information, age of onset of SLE, disease and follow up duration, clinical and laboratory variables and outcome. The patients from the familial group were younger and had an earlier age of onset of disease (P = 0.03, 0.001 respectively). Seven patients with familial SLE were from the eastern region of Saudi Arabia (P = 0.006). The two groups were comparable with respect to gender, disease duration and follow-up. At diagnosis, the discoid rash was more frequent in the familial group (P = 0.03) while other clinical and laboratory variables including disease activity as measured by SLEDAI did not show significant differences. The mean dose of steroid and use of other immunosuppressive therapy were similar in both groups. Three patients from the familial group died; two of them had unusual complications (one patient had transverse myelitis and pancreatic pseudocyst and the other one had extensive pyoderma gangrenosum). All patients from the sporadic group are alive in stable condition but one patient had severe central nervous system disease. Familial SLE patients tend to be younger and more likely to have discoid rash, in addition a marked difference in the origin of patients was noted. These differences may be helpful in identifying SLE patients with a stronger genetic predisposition. The mortality among familial SLE patients is more frequent which may reflect the disease severity.     

Similar clinical characteristics of familial and sporadic inflammatory bowel disease in South Korea

AIM:To investigate differences of clinical characteristics and disease courses between familial and sporadic inflammatory bowel disease(IBD)patients.METHODS:We obtained clinical data on Crohn’s disease(CD)(n=691)and ulcerative colitis(n=1113)from a tertiary referral medical center between 2005and 2012.Seventeen patients(2.5%)with CD and27 patients(2.4%)with ulcerative colitis(UC)were identified as having a familial history of IBD,including the first and second degree relatives.For each control case,three times the number of age-,sex-,and diagnosis year-matched CD and UC patients,without a family history of IBD,were randomly selected in this case control study.RESULTS:There were no significant differences in age or main symptom at diagnosis,extraintestinal manifestation,location/extent,behavior of disease activity,number of hospitalizations,number of operations,operation type,number of relapses,or oral medical treatment between familial and sporadic CD and UC patients.Median(min-max)follow-up periods after diagnosis of familial CD and sporadic CD patients were 84(24-312)and 36(8-240)mo,respectively(P=0.008).Familial CD patients more frequently used anti-tumor necrosis factor(TNF)antibodies compared to sporadic CD patients(17.6%vs 0%,P=0.014).CONCLUSION:In conclusion,a family history of IBD does not seem to be an important predictive factor affecting clinical characteristics or disease course even if there is a more frequent use of anti-TNF antibodies in familial CD patients compared to sporadic CD patients.     

Familial articular chondrocalcinosis in Spain.

One hundred and one first degree relatives of 35 patients with chondrocalcinosis were examined for the presence of familial disease. Eleven subjects from nine families showed radiological chondrocalcinosis, a prevalence of familial disease of 26%. Two different patterns of disease were noted--the older generation was more commonly affected, and the younger generation and second degree relatives were exempt. Clinical and radiological differences were found between the early and late onset groups, but not between late onset and sporadic forms of chondrocalcinosis. These findings support the suggestion that the true prevalence of familial disease. is underestimated. A dominant, autosomal transmission with variable penetrance is consistent with our findings, which suggests that homozygous patients with familial chondrocalcinosis may present a more severe form of the disease.     

Variation at NOD2/CARD15 in familial and sporadic cases of Crohn's disease in the Ashkenazi Jewish population

OBJECTIVE: Recent reports indicate that allelic variants in NOD2/CARD15 are associated with Crohn's disease (CD) susceptibility, and that homozygosity or compound heterozygosity at this locus for any of three recently defined sequence variants confers a greatly increased risk of CD. These sequence changes include two missense mutations, R702W and G908R, and a frameshift insertion, 1007insC. The aim of this study was to determine the frequency of these NOD2/CARD15 variants in familial and sporadic CD patients in the Ashkenazi population and to determine their effects on disease susceptibility and age of disease onset (AOO). METHODS: Allele and genotype frequencies of these three variants were determined in 481 CD patients of Jewish descent and 110 Jewish controls; 169 patients had a family history of CD, and 312 were "sporadic" cases. Variants were detected by polymerase chain reaction using allele-specific primers labeled with fluorescent dye. RESULTS: Familial cases had a significantly higher frequency of the G908R variant than sporadic cases (0.127 vs 0.059, p = 0.0003) and correspondingly, a significantly higher proportion of homozygotes and compound heterozygotes (11.8% vs 4.5%, p = 0.0027). Homozygotes and compound heterozygotes had an OR for CD of 14.6 for familial cases and 5.1 for sporadic cases. There was no increased risk of CD for simple heterozygotes. The AOO was significantly lower for CD patients who were homozygotes and compound heterozygotes for NOD2/CARD15 (17.5 vs 22.4 yr, p = 0.04), but only for familial cases. CONCLUSIONS: NOD2/CARD15 contributes more to CD susceptibility in familial cases than in sporadic cases, and to an earlier AOO. There is no increased risk of CD for individuals carrying only a single copy of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5-15-fold increased risk. The penetrance of the NOD2/CARD15 mutations was estimated at less than 1%.     

Familial acute myeloid leukaemia: four male members of a single family over three consecutive generations exhibiting anticipation

A kindred with familial acute myeloid leukaemia (AML) is described displaying the concept of anticipation which refers to increased disease severity and/or earlier age at onset with succeeding generations. The affected individual in the first generation was the father (aged 34 years at diagnosis) of two affected members of a single sibship (aged 24 and 25 years). The fourth patient is the son (aged 4 years) of one of these brothers in the second generation. The AML was of different subtypes and a karyotypic abnormality (del[6q]) was detected in one of three patients. The first-generation patient died during chemotherapy; the remaining three patients are in complete remission after chemotherapy and autologous bone marrow transplantation.