Familial versus sporadic ankylosing spondylitis. two different diseases?

Objective. To define potential differences and the possible contribution of susceptibility or severity genes in familial versus sporadic ankylosing spondylitis (AS). Methods. Three hundred twenty patients with AS were studied: 160 who had first-degree relatives with AS (familial) and 160 age- and sex-matched controls who had no first-degree relative with the disease (sporadic). Disease expression in the two groups was evaluated using an index of physical, psychological, and social functioning (the Arthritis Impact Measurement Scales [AIMS]) and an assessment of spinal mobility. Results. Familial disease was significantly milder than sporadic disease as assessed by all measures, e.g., spinal mobility score (mean 4.08 versus 4.65, P < 0.038), AIMS overall impact score (mean 2.63 versus 3.59, P = 0.002), AIMS physical activity score (4.19 versus 5.10 [P = 0.004]), AIMS social function score (4.02 versus 4.60, P = 0.023), and AIMS pain score (4.15 versus 5.33, P = 0.002). Conclusion. The greater prevalence of AS in at-risk families may be explained by the occurrence of more AS “susceptibility” genes in those families, whereas the more severe disease, seen in patients with sporadic AS, is conferred by the presence of more “severity” genes than “susceptibility” genes.     

Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study

BACKGROUND: Genetic factors may play a role in determining the development of extraintestinal manifestations (EIMs) and autoimmune diseases (AD) in patients with inflammatory bowel disease (IBD). We sought to determine the association between EIMs and AD in patients with first-degree familial IBD and sporadic IBD. METHODS: All patients evaluated in the IBD Clinic at the Mayo Clinic between January and September 1999 were offered enrollment. One clinic patient who was matched on age, gender, and geographic area of residence to each case served as controls. Information regarding EIMs and AD was obtained from a questionnaire completed by all IBD patients and controls. The adjusted odds ratios (95% CIs) for EIM as a function of first-degree familial IBD compared with sporadic IBD and AD as a function of first-degree familial IBD compared with sporadic IBD were estimated with a matched one-to-one conditional logistic regression model. RESULTS: Two hundred forty-three patients with IBD (47 first-degree familial IBD, 196 sporadic IBD) were enrolled. Forty percent of IBD patients had one or more EIMs compared with 14% matched controls [p < 0.001; OR = 3.1 (95% CI: 1.8 to 5.2)]. A total of 259 of the 1122 IBD patients and their first-degree family members indicated one or more EIM diagnoses (23%). The association between "familial versus sporadic" status and any EIM diagnosis was not significant [p = 0.59, the odds for an individual from a familial IBD family relative to an individual from a sporadic IBD family was 1.2 (95% CI: 0.8 to 1.7)]. Ten percent of IBD patients had one or more AD diagnoses compared with 19% matched controls [p = 0.04; OR = 0.4 (95% CI: 0.1 to 0.96)]. A total of 153 of the 1122 IBD patients and their first-degree family members indicated one or more AD diagnoses (14%). The association between disease status ("familial or sporadic") versus any AD diagnosis was not significant [p = 0.68, the odds for any AD in an individual from a familial IBD family relative to an individual from a sporadic IBD family was 1.4 (95% CI: 0.9 to 2.3)]. CONCLUSIONS: There was a positive association between IBD status (patient vs control) versus EIM, but not AD. A significant positive association between disease type (familial or sporadic) versus either EIM or AD was not detected.     

Clinical, immunologic, and genetic features of familial systemic sclerosis

OBJECTIVE: To examine whether the affected first-degree relatives within multicase systemic sclerosis (SSc; scleroderma) families are concordant for autoantibody profile, disease type, and HLA class II haplotypes and whether clinical expression and serologic characteristics of familial SSc differ from those of sporadic SSc. METHODS: Seven hundred ten SSc families from the Scleroderma Family Registry and DNA Repository (Scleroderma Registry) were examined, and 18 multicase families were identified. SSc cases and their first-degree family members underwent serologic testing for different autoantibodies. The disease type and various disease features were abstracted from the available medical records. Additionally, HLA class II typing was performed on the multicase SSc sibpairs. RESULTS: The observed SSc-specific antibody concordance within each multicase SSc family was statistically more common than expected by chance alone (P = 0.007). The autoantibody profile and disease features of familial and sporadic SSc cases did not differ significantly. The frequency of autoantibody positivity was not different between unaffected first-degree family members of patients from multicase versus singleton SSc families. HLA haplotype sharing between SSc sibpairs was significantly more common than expected (P = 0.011). CONCLUSION: The affected members within multicase SSc families tend to be concordant for SSc-specific autoantibodies and HLA haplotypes; familial SSc does not appear to be a unique disease subset.     

Clinical characteristics of familial versus sporadic Crohn's disease using the Vienna Classification

BACKGROUND: The etiology of Crohn's disease, an illness protean in its manifestations, may be better resolved through studies involving more homogenous subgroups of patients. Because a strong genetic influence exists, family history of inflammatory bowel disease may be a useful variable for patient classification if patients with familial and sporadic Crohn's disease are clinically different. Our study attempted to define any possible differences. METHODS: The medical records of 552 patients were reviewed, and patients were classified according to guidelines of the Vienna Classification. Patients were then divided based on family history of inflammatory bowel disease, and the familial and sporadic groups were compared. RESULTS: Overall, 422 (78.9%) patients were diagnosed before age 40 years (A1) and 114 (21.1%) at age 40 years or older (A2). There were 141 (26.3%) patients with disease involving the terminal ileum only (L1), 211 (39.4%) in the colon only (L2), 117 (21.9%) in the terminal ileum and colon (L3), and 66 (12.3%) in the upper gastrointestinal tract (L4). Disease behavior, as determined at the time of last visit or telephone contact, was nonstricturing, nonpenetrating (B1) in 149 (27.9%) patients, stricturing (B2) in 50 (9.3%) patients, and penetrating (B3) in 336 (62.8%) patients. Comparisons among the groups of 53 patients with first-degree relatives only, the 96 patients with either first-, second-, or third-degree relatives (familial CD group), and the 439 patients with sporadic disease demonstrated no differences in sex, age at diagnosis, or disease location. There was a difference in disease behavior between the familial and sporadic groups (p = 0.048) that failed to exist when nonstricturing, nonpenetrating cases were excluded. No such difference was observed between the first-degree relatives only group and the sporadic group (p > 0.10). CONCLUSIONS: Using the Vienna Classification, familial and sporadic Crohn's disease differed only in disease behavior. However, this difference failed to exist after patients with nonstricturing, nonpenetrating disease were excluded. Therefore, familial and sporadic groups appear to be quite similar clinically, and family history does not appear to be a variable useful for disease subclassification.     

Familial aggregation of ankylosing spondylitis in Southern China

OBJECTIVE: To study the familial aggregation of ankylosing spondylitis (AS) in southern China and to compare the clinical and laboratory characteristics between the probands and their first-degree relatives with AS. METHODS: On the basis of questionnaires to 473 patients with AS, 402 responded and 36 self-reported having first-degree relatives with symptoms related to spondyloarthropathies. All together, 144 of 150 first-degree relatives of these 36 probands were examined for clinical and radiographic characteristics. HLA typing for HLA-B27 was performed by standard microlymphocytotoxicity method. RESULTS: The disease duration of the 36 probands was 5.03 +/- 3.76 years (0.5-14 yrs). Forty seven first-degree relatives of the 36 probands were diagnosed as having AS. The prevalence of AS among the first-degree relatives of these 36 aggregated families was 31.3%. The overall prevalence of AS among the first-degree relatives in these 402 families was estimated to be 2.8%. The recurrence risk of the first-degree relatives within these aggregated families was 31.3%, suggesting an excess risk to them of 120.4, while it was 10.8 to the general families. The probands more often had peripheral arthritis and enthesopathies (p < 0.001 and p = 0.01, respectively) than the AS patients among the first-degree relatives. HLA-B27 was associated with development of AS in the probands and the patients among the first-degree relatives. CONCLUSION: Although familial aggregation of AS in southern China is uncommon in general, the recurrence risk of the first-degree relatives of AS probands within the aggregated families is extremely high, according to our study among hospital based patients. As the disease of the first-degree relatives is often mild and atypical, familial background analysis should be encouraged to assist early diagnosis.     

Familial and sporadic inflammatory bowel disease: different entities?

The strongest risk factor for developing inflammatory bowel disease (IBD) is having a relative with the disease. Familial IBD may be one homogeneous subgroup, phenotypically different from sporadic IBD. Several observations support a role for familiarity in disease site and behavior, particularly in Crohn's disease (CD), but published findings do not all concur. Early disease onset is often found in children with IBD who have a parent with the disease. Genetic anticipation may explain this finding but other explanations and/or observational biasis are more likely. Location and type may differ between familial and sporadic CD cases: family studies report many cases involving both small bowel and colon, and few cases of colonic disease alone, although such features may be secondary to early age at onset. Most studies found no effect of positive family history on severity and course of CD. In ulcerative colitis (UC), phenotypic differences between familial and sporadic cases appear to be limited, but little data are available for analysis. No difference has been found between familial and sporadic IBD as far as disease markers such as pANCA, ASCA, or intestinal permeability are concerned. In conclusion, the only message available for clinical practice is that the relative risk of IBD in first-degree relatives is increased by a factor of 10-15 compared with the general population. Families should not receive genetic counseling/information about age at onset and disease severity.     

Are there any differences in phenotype or disease course between familial and sporadic cases of inflammatory bowel disease? Results of a population-based follow-up study

BACKGROUND: The influence of familial IBD on phenotype and course of disease in patients with CD and UC has not been studied in population-based cohorts. AIM: To compare phenotype and course of disease between IBD patients with a first-degree relative with IBD and sporadic cases in a population-based cohort followed prospectively for 5 yr. METHODS: Family history of IBD was registered at diagnosis and after 1 and 5 yr. Phenotype and course of disease were compared between sporadic and familial cases. RESULTS: Data for 200 patients with CD and 454 with UC were sufficient for analysis. A first-degree relative with IBD was registered in 14.5% of CD patients and 10.1% of UC patients. The concordance for type of disease was 82% and 70% for CD and UC, respectively. No differences between familial and sporadic cases as regards localization and behavior of disease in CD patients or disease extent in UC patients were observed. In CD patients with colonic involvement, those in the familial group were significantly younger at diagnosis than the sporadic cases. No difference in disease severity in CD patients was observed between the familial and sporadic groups. In UC patients relapse was more frequent in familial cases, but no difference was observed in the need for surgery or medical treatment. CONCLUSIONS: A family history of IBD does not seem to influence phenotype or to be an important prognostic factor for disease course in IBD patients.     

Familial and sporadic hypertrophic myopathy: differences and similarities in a genotyped population. A long follow-up study

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disease associated with mutations in genes encoding cardiac sarcomere proteins. A mutation is identified in two-thirds of cases, and more frequently in familial forms. Doubts remain concerning the true identity of the sporadic form. OBJECTIVE: To compare, in a genotyped population, the phenotypic expression of the disease over time in patients with familial and sporadic HCM. METHODS: 79 patients with HCM, aged 39 +/- 17.8 years at diagnosis, were followed for 12 +/- 9.5 (1-30) years and divided into two groups: G1 (familial)--68 patients (24 unrelated index patients, 44 relatives), follow-up time (FUP) 12 +/- 9.8 (1-30) years; G2 (sporadic)1 index patients (no phenotypic disease in first-degree relatives), FUP 10.8 +/- 8 (2-24) years. Fabry disease was excluded in G2. The two groups were compared regarding clinical, ECG and echocardiographic (echo) features at diagnosis and after FUP. Five sarcomere genes (MYH7, MYBPC3, TNNT2, MYL2 and TNNI3) were screened for mutations by direct sequencing, after PCR amplification with intronic sets of oligonucleotide primers designed according to the published genomic sequence of the genes. RESULTS: A) Thirteen different mutations (in 3 genes) were identified in 14 index patients in G1; only in one patient in G2 was a mutation found. B) The two groups differed clinically in age at diagnosis (G1: 37.18 (4-79) years; G2: 51 +/- 14 (19-67) years; p = 0.02), and family history of sudden cardiac death (G1: 12/24 families; G2: 1/11 families; p = 0.04). Age, gender, FUP, symptoms, need for medical treatment, cardiovascular (CV) hospitalization and mortality (CV or any cause) were similar. C) ECG patterns did not differ, although significant (but similar) changes occurred in 45% (G1) and 36% (G2) of patients (p = 0.75). These changes were in the same direction, with a trend in both groups toward the development of atrial fibrillation and/or advanced conduction disease. D) Echo features (only considered in adults) were similar despite significant changes during FUP (in 68% of G1, and 82% of G2; p = 0.48). These changes also followed the same tendency: progression to a more diffuse pattern of ventricular hypertrophy (G1: 52%; G2: 73%; p = 0.33) and development of left atrial dilatation (G1: 37%; G2: 45%; p = 0.52). CONCLUSIONS: The similar phenotypic expression and behavior over time in familial and sporadic forms of HCM strongly indicate that the disease is one and the same. Differences in genetic findings, age at diagnosis and family history of sudden death suggest that sporadic forms may be caused by low penetrance de novo mutations in sarcomeric genes other than those associated with familial disease.     

Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands

OBJECTIVE: To estimate in a Chinese population the prevalence of undifferentiated spondyloarthropathy (USpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) probands, and to compare the clinical features of familial USpA with those of sporadic USpA. METHODS: The FDRs of two separate cohorts of consecutive AS probands were evaluated for the prevalence of USpA, using the Modified New York criteria and the European Spondylitis Study Group criteria for AS and SpA, respectively. Sporadic USpA and FDRs of non-SpA rheumatic patient probands served as separate controls. RESULTS: Among the 301 FDRs of 102 AS probands, 7.0% were USpA. This was 1000 times higher than the 147 FDRs of 40 non-SpA probands (P = 0.00230). Within the AS families, USpA was less male-dominated than AS (33.3 vs 72.5%) (P = 0.006). The only feature distinguishing familial from sporadic USpA was that the percentages of HLA B27 were 100 and 50%, respectively (P<0.001). CONCLUSION: USpA and AS coexist in the same Chinese families, both being predisposed by HLA B27. In these families, a female gender favours the development of USpA rather than AS. A significant subset of sporadic USpA (HLA B27-negative group) has a different genetic predisposition compared with familial USpA.     

Familial vs sporadic rheumatoid arthritis (RA). A prospective study in an early RA inception cohort

OBJECTIVES: To study potential differences in demographic, process and outcome variables between familial and sporadic rheumatoid arthritis (RA) in an early RA inception cohort. METHODS: In 1998, we ascertained the familial status of all collaborative patients in a large early RA inception cohort at our department. Familial RA was defined by the presence of at least two siblings fulfilling the American College of Rheumatology criteria for RA. Baseline demographic data and prospectively recorded disease activity variables, therapies and radiological damage during the first 6 yr of disease were included in the analysis. A regression analysis was performed to assess whether familial clustering is a prognostic factor. RESULTS: We identified 142 patients with sporadic and 36 with familial RA. The most striking difference between these groups was the larger sibship size in multicase families (8.2 +/- 2.5 vs 5. 5 +/- 2.8; P < 0.0001). Age at onset was similar in both groups, although males with familiar RA were younger at disease onset than those with sporadic RA (median 50 vs 57 yr; P=0.03). No differences were found in gender, presence of rheumatoid factor (RF), antinuclear factor and HLA-DR typing or in disease activity, interventions and outcome over 6 yr of follow-up. Early radiological damage and disease activity, but not familial history of RA were prognostic for X-ray damage. CONCLUSION: We show that sibship size is the only relevant risk factor for familial RA. No differences in genotypic and phenotypic characteristics, disease severity or radiological damage were observed among familial and sporadic RA. Familial history of RA is not a poor prognostic factor. This prospective study confirms previous cross-sectional findings in the Dutch population.     

Familial systemic lupus erythematosus in Finland

OBJECTIVE: To perform a cross sectional nation-wide clinical study of familial systemic lupus erythematosus (SLE) in Finland. METHODS: We sought to identify all Finnish families in which at least 2 members satisfied the classification criteria for SLE. About 1,200 patients with SLE (80-85% of all patients attending Finnish hospitals) were contacted. Personal and/or phone interviews and examination of medical records were used to verify the diagnoses. A comparison of clinical characteristics was made between familial cases of SLE and matched sporadic controls. RESULTS: We identified 53 multiplex families with 113 SLE patients. Forty-six families had 2 affected members and 7 families had 3 affected members. There were 3 pairs of monozygotic female twins and one pair of dizygotic twins of the opposite sex concordant for SLE. Eleven (9.7%) of the 113 familial cases of SLE were male. No differences were found in the clinical presentation of SLE between familial and sporadic cases (sex, age at onset, major clinical manifestations, and common laboratory tests). The incidence of familial SLE was approximately 4-5%. CONCLUSION: Our study shows that familial and sporadic SLE are not different disease entities; this means that we can extrapolate the results of future genetic analyses in multiplex SLE families to all patients with SLE.     

Comparison of clinical and laboratory variables in familial versus sporadic systemic onset juvenile idiopathic arthritis

OBJECTIVE: To compare patients with familial versus sporadic juvenile idiopathic arthritis (JIA) with respect to clinical and laboratory variables. METHODS: The familial JIA group comprised 11 affected siblings belonging to 4 families, while the comparative group comprised 22 patients selected by systematic sampling from JIA patients presenting to our pediatric rheumatology clinic; the first patient was chosen randomly and the subsequent patients chosen at intervals of 3. The 2 groups were compared with respect to demographic information, age at onset of disease, disease activity, disease damage, and laboratory variables. RESULTS: The 2 groups were comparable with respect to age, sex, and onset type of disease. All patients from the familial group were from a southern province of Saudi Arabia (p = 0.001). The familial group had an earlier age at onset of disease (p = 0.039), the mean number of actively inflamed joints was higher (p = 0.009), and functional capacity as measured by Childhood HAQ was worse (p = 0.048), compared with the sporadic group. Other variables showed no significant differences. CONCLUSION: The comparison of patients with familial versus sporadic JIA revealed a significant difference in origin of patients and age at onset of disease. These differences may be helpful in identifying the predisposing genes in familial patients with JIA.     

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.     

Monoclonal B-cell lymphocytosis in first-degree relatives of patients with sporadic (non-familial) chronic lymphocytic leukaemia

Although biological similarities have been described among monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukaemia (CLL), the relationships between these two conditions are not fully understood, and new epidemiological studies in different populations and different countries continue to be reported. Here, we investigated 167 first-degree relatives from 42 families of patients with non-familial (sporadic) CLL, using four-colour flow cytometry. MBL was found in seven of 167 subjects (4·1%). Monoclonality was detected in all cases either by light-chain restriction or by polymerase chain reaction. Fluourescence in situ hybridization did not show any chromosomal abnormality. The prevalence of MBL according to age was 0 (0/54) in individuals aged less than 40 years, 2·5% (2/81) between 40 and 60 years, and 15·6% (5/32) in individuals over 60 years. The prevalence of MBL cases in individuals over 60 years was similar to that found in familial CLL relatives at the same age group. This suggests that in older first-degree relatives of patients with sporadic CLL, the risk of MBL detection is as high as in older first-degree relatives from CLL families, which could render these individuals belonging to 'sporadic CLL families' as susceptible as individuals from 'familial CLL' to the development of clinical CLL.     

Familial and sporadic inflammatory bowel disease: comparison of clinical features and serological markers in a genetically homogeneous population

BACKGROUND: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. METHODS: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. RESULTS: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) (P< 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA+ yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCA- of 55%, 94% and 90%, respectively, for UC. CONCLUSIONS: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.     

Familial and Sporadic Inflammatory Bowel Disease: Comparison of Clinical Features and Serological Markers in a Genetically Homogeneous Population

Background: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. Methods: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. Results: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases, CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) ( P < 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA + yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCAof 55%, 94% and 90%, respectively, for UC. Conclusions: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.     

Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis?

Objective

Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome‐wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants.

Methods

Overall, 502 AS patients were examined, consisting of 312 patients who had first‐degree relatives (FDRs) with AS (familial) and 190 patients who had no FDRs with AS or spondylarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York criteria for AS. The patients were recruited from 2 US cohorts (the North American Spondylitis Consortium and the Prospective Study of Outcomes in Ankylosing Spondylitis) and from the UK‐Oxford cohort. The frequencies of AS susceptibility loci in IL‐23R, IL1R2, ANTXR2, ERAP‐1, 2 intergenic regions on chromosomes 2p15 and 21q22, and HLA–B27 status as determined by the tag single‐nucleotide polymorphism (SNP) rs4349859 were compared between familial and sporadic cases of AS. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size.

Results

HLA–B27 was significantly more prevalent in familial than sporadic cases of AS (odds ratio 4.44 [95% confidence interval 2.06, 9.55], P = 0.0001). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend toward higher frequency in the multiplex cases (P = 0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined.

Conclusion

HLA–B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA–B27 positivity. The frequency of the recently described non–major histocompatibility complex susceptibility loci is not markedly different between the sporadic and familial cases of AS.     

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.     

Immunogenetic differences between patients with familial and non-familial rheumatoid arthritis

OBJECTIVE: To search for possible immunogenetic differencies between the patients with familial and non-familial rheumatoid arthritis (RA). METHODS: The study compared 129 familial RA patients with 217 non-familial patients for the frequencies of HLA-DR antigens including DR4 subtypes, DR4-DQB1*0301 and DR4-DQB1*0302 haplotypes and HLA-B27 antigen as well as the age of disease onset and existence of rheumatoid factor or joint erosions. RESULTS: Two major differences between familial and non-familial groups were found: firstly, familial RA patients had increased frequency of HLA-DR4 as compared with the non-familial RA group (68.2 v. 54.8%; p = 0.019). Secondly, the mean age at onset of RA was significantly lower in the familial than in the sporadic RA patients (42.0 v. 46.5 years; p = 0.0020) and the difference still remained when the DR4 positive and negative subgroups were compared separately. CONCLUSION: These results confirm the more prominent association with HLA-DR4 in familial than in the non-familial cases and suggest that accumulation of HLA risk genes may, at least partly, explain the familial occurrence of the disease. Other susceptibility genes may also be concentrated in multiplex case families as suggested by an earlier age at the onset of RA in both HLA-DR4 positive and negative familial patients.     

Equivocal and borderline myocardial hypertrophy in relatives of patients with hypertrophic cardiomyopathy: possible implications in genetics of the disease

To determine the occurrence of familial and sporadic forms of hypertrophic cardiomyopathy (HC) 74 first-degree relatives of 21 patients with proven HC were studied by M-mode and two-dimensional echocardiography. A diagnosis of HC was made in 11 relatives (15%) while it was excluded in 61 of them (82%); 2 subjects (3%) were considered neither affected nor unaffected (borderline left ventricular hypertrophy suggestive of HC). Inspection of pedigrees revealed 38% of familial forms of HC with an autosomal dominant pattern of inheritance in 5/8 families (62%). Furthermore, among those relatives judged unaffected by means of full echocardiographic criteria for HC, an attempt was made to find out whether minor changes of left ventricular geometry were present for their possible implications in genetics of HC (latent or potential forms, low phenotypic expression of the disease). Eleven out of 61 unaffected relatives had a left ventricular wall thickness radius ratio greater than 0.50 (equivocal hypertrophy), a value that was higher than two standard deviations of the control group. Assessment of clinical significance of borderline and equivocal hypertrophy in relatives of patients with HC is required for a better understanding of genetic transmission of this disease. In this view the occurrence of sporadic and familial forms of HC might be revisited.