Familial chondrocalcinosis in the Spanish population

We have found in our clinic a 28.1% prevalence of familial chondrocalcinosis among 149 family members of 32 patients with calcium pyrophosphate dihydrate deposition disease. The clinical and radiological characteristics of these familial chondrocalcinosis patients were similar to those of the Chiloes with familial chondrocalcinosis previously reported. No significant clinical or radiological differences were detected between our sporadic and familial chondrocalcinosis patients. Our findings support the hypothesis that the Chiloes familial chondrocalcinosis was carried to Chile by Spanish immigrants.     

Radiographic features of hereditary articular chondrocalcinosis. A comparative study with the sporadic type

To assess the radiological features of hereditary articular chondrocalcinosis, we performed a blind comparative study between 21 randomly selected patients with hereditary disease and 21 cases of sporadic pseudogout matched for age and sex. Each individual had AP projections of the hands, pelvis and knees. The films were evaluated for the presence of articular chondrocalcinosis and for the severity of the associated degenerative arthropathy. A grade of 0 to 3+ was assigned to each of the 4 variables of osteoarthritis: joint space narrowing, sclerosis, osteophytosis and subchondral cysts. The mean number of joints with chondrocalcinosis and its distribution was similar in both groups. In addition, no differences were found in the overall severity of the associated degenerative arthropathy. In both groups the disease was characterized by oligoarticular calcification and a mild degenerative arthropathy. These data along with data from other reported pedigrees, show that the radiological appearance in the hereditary type is frequently indistinguishable from that commonly observed in sporadic articular chondrocalcinosis.     

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.     

Pediatric granulomatous arthritis: an international registry

OBJECTIVE: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis, share an identical phenotype featuring the classic triad of arthritis, dermatitis, and uveitis and are associated with mutations of CARD15 in 50-90% of cases. We chose the term "pediatric granulomatous arthritis" to refer to both. An international registry was established in the spring of 2005 to define the phenotype spectrum and establish the mutation frequency and variants. METHODS: Histologically confirmed granuloma and arthritis were required for inclusion. Probands and relatives were genotyped for CARD15. Deidentified clinical information was collected. RESULTS: One year after the inception of the registry, 61 individuals from 22 pedigrees had been entered. Seven pedigrees with 19 individuals (8 affected, 11 unaffected) had clinical disease that was atypical, and none of the individuals in those pedigrees showed mutations. There were 9 classic simplex pediatric granulomatous arthritis pedigrees including 19 individuals (9 affected, 10 unaffected) and 6 classic multiplex pedigrees with 22 individuals (17 affected, 5 unaffected). Cutaneous presentation was the most common. Arthritis was polyarticular in 96% of patients. Isolated eye disease was never the presenting symptom, but significant/severe visual impairment was observed in 41% of patients. Eye disease was bilateral in 21 of 22 patients and was complicated by glaucoma in 6 of 22 patients and by cataracts in 50% of patients. Skin biopsy was the best diagnostic approach (because of accuracy and low invasiveness). CONCLUSION: In this series, the first combining familial and sporadic pedigrees and, to our knowledge, the largest, we further defined the phenotype and showed that all affected classic (and no nonclassic) pedigrees carry a mutation and that there is no asymptomatic carriage. If these data are confirmed, mutation analysis rather than tissue sampling may prove to be the most efficient diagnostic procedure.     

Significance of the RET proto-oncogene polymorphisms in Turkish sporadic medullary thyroid carcinoma patients

Several single nucleotide polymorphisms (SNP) of the RET gene have been identified in medullary thyroid carcinoma (MTC) patients as well as in the general population. However, the relevance of SNP for MTC patients is still controversial, whether these allelic variants play other interacting, predisposing or modifying roles in clinical behavior of MTC. The aim of this work is to elaborate allelic frequencies of the RET proto-oncogene polymorphisms in Turkish sporadic MTC patients and to demonstrate if there is an association between SNP and the clinical disease features, specifically the age at onset of MTC and lymph node involvement at diagnosis. We analyzed the allelic frequencies of SNP of the exon 11, 13, 14 and 15 of the RET proto-oncogene in blood samples from 50 sporadic MTC patients, using the polymerase chain reaction methodology followed by DNA sequencing. The observed allelic frequencies were 24% for G691S polymorphism in exon 11, 29% for L769L polymorphism in exon 13, 5% for S836S polymorphism in exon 14, and 26% for S904S polymorphism in exon 15. These frequencies are similar to those reported in other countries. We did not observe any significant association of all four SNP with the age at onset of MTC. Our results indicate a possible association between the presence of lymph node involvement at the time of diagnosis (extent of disease) and L769L or S836S polymorphism. However, it is not possible to draw definitive conclusions that these two polymorphisms play a significant role in clinical behavior of MTC. Further studies are needed to evaluate the role of this polymorphism in the clinical behavior of MTC.     

Chondrocalcinosis in primary hyperparathyroidism. Influence of age, metabolic bone disease, and parathyroidectomy.

Chondrocalcinosis is known to be common in hyperparathyroidism. In order to discover the effect of parathyroidectomy on chondrocalcinosis and to investigate this association further, we studied two groups of patients. In one group were 41 postparathyroidectomy patients, and in the other 100 admissions to the acute geriatric unit. The total incidence of chondrocalcinosis in the parathyroidectomy group was 32%, and in the elderly control group 11%. There was little or no osteoarthrosis in these patients. It was found that chondrocalcinosis occurred in the normal population from the age of 75 and in the hyperparathyroid group from the age of 45. In both groups the incidence rose steadily with age. In the hyperparathyroid group alone, preoperative serum calcium levels were no different in those without chondrocalcinosis, suggesting that hypercalcaemia alone is not a sufficient stimulus for chondrocalcinosis. Those with chondrocalcinosis had higher mean preoperative alkaline phosphatase levels, nearly twice as much radiological bone disease, and were older. Parathyroidectomy had no effect on attacks of pseudogout or on preexisting cartilage calcification. A connection with high levels of circulating parathyroid hormone is suggested, and a link with physical age-related changes in cartilage postulated.     

Sporadic and epidemic nosocomial legionellosis in the United States: Epidemiologic features

As of April 30, 1980, 83 nosocomial cases of sporadic legionellosis had been reported to the Centers for Disease Control (CDC). In all 83 cases the patients had pneumonia; the median age of the patients was 56.5 years. All but one patient were hospitalized at the time of onset. Of 71 patients for whom the outcome is known, 22 (31 percent) died of causes directly attributed to their infection. Eleven patients had end-stage renal disease, 28 were receiving systemic immunosuppressive medications, 17 had cancer, 12 had chronic bronchitis or emphysema, 29 were smokers, and four had diabetes mellitus. Risks of acquiring nosocomial sporadic legionellosis for patients with these conditions relative to the general United States population = 340, 26, 11, 3.7, 1.9 and 1.3, respectively. These risk factors are similar to those identified for sporadic community-acquired legionellosis and for epidemic nosocomial legionellosis. Methods for preventing nosocomial legionellosis are not known, but comparing Legionella to other water-associated organisms which have been spread from medical devices to cause pneumonia may be fruitful.     

Familial chondrocalcinosis

The first-degree consanguineous relatives of 46 patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease were examined for the presence of articular chondrocalcinosis. In 5 cases the process was familial, with 17 persons in the oldest living generation (mean age 69 ± 7.4) showing radiographic evidence of calcified cartilage. The clinical syndrome was characterized by a female predominance, late onset of symptoms with mild arthritic manifestations, and oligoarticular chondrocalcinosis. These data suggest that the familial type of CPPD crystal deposition disease is more frequent than formerly thought.     

Crohn's Disease in the Elderly

To determine the features of Crohn's disease in elderly patients we reviewed the charts, roentgenograms and pathology of patients with Crohn's disease admitted to our hospital from 1966 through 1979. Thirty-three patients (5.2% of the total) had the onset of symptoms and diagnosis made after age 60, including 18 (55%) with ileitis alone, 11 with colitis and four with ileocolitis. Six patients were seen, four with colitis and two with ileocolitis, with acute toxicity requiring early surgery. The clinical, radiographic and histologic characteristics of the disorder in older patients were otherwise similar to those described in younger patients. Differentiation of ischemic bowel disease and diverticulitis from Crohn's disease in such patients was difficult without reliance on histologic as well as clinical and roentgenographic features. Fifty-eight per cent of these older patients eventually required surgery, including 10 of 11 (91%) with colitis, two of four with ileocolitis and seven of 18 (39%) with ileitis. The cumulative clinical recurrence rate, limited to patients with ileal disease, was 21% at nine years and 37% at 15 years.     

Calcium pyrophosphate crystal deposition disease and hyperparathyroidism: a controlled, prospective study.

A prospective, controlled study of patients with primary hyperparathyroidism has been carried out to establish the relation of this endocrinopathy to calcium pyrophosphate dihydrate crystal deposition disease. Eight of 26 patients with documented hyperparathyroidism were found to have chondrocalcinosis compared to four of 104 individuals in the control group (p less than 0.01). Two of these eight patients had confirmed pseudogout attacks shortly after parathyroidectomy. Four other patients, including two without chondrocalcinosis, gave a history of typical pseudogout. Patients with hyperparathyroidism and chondrocalcinosis were significantly older than those without the articular lesion (p = 0.006). We could not delineate specific metabolic abnormalities of hyperparathyroidism which contributed to the development of chondrocalcinosis.     

Early clinical differentiation between Legionnaires' disease and other sporadic pneumonias.

Early diagnosis of Legionnaires' disease is difficult because other pathogens cause a similar clinical picture and microbiologic tests are usually only of retrospective value. Since May 1977, 17 patients with sporadic cases of Legionnaires' disease have been admitted, all previously well, the diagnosis being made with standard serologic or bacteriologic criteria. From the clinical, laboratory, and radiologic findings, we propose criteria that may enable the clinician to make a diagnosis earlier in many cases, differentiating them from other pneumonias. Within 24 hours of admission, any three of the following four features are strongly suggestive of Legionnaires' disease: [1] prodromal "viral" illness, [2] dry cough or confusion or diarrhoea, [3] lymphopenia without marked neutrophilia, [4] hyponatremia. Two thirds of cases had at least three of these features, and no false-positive diagnoses would have been made in other pneumonias that were serologically negative for Legionnaires' disease if these proposed criteria had been applied diagnostically. In the next few days the diagnosis is very likely if microbiologic tests are negative and if there is radiologic extension, abnormal liver function test results, or hypoalbuminemia.     

Hereditary chondrocalcinosis in a Tunisian family.

A clinical and radiological survey of 77 members of a Tunisian family with hereditary chondrocalcinosis was performed. Articular chondrocalcinosis was documented by X-rays in 7 living members of 3 generations. No associated or secondary forms of the disease were found. Clinical features of the disease appeared early in life and radiologic involvement was extensive. The mode of inheritance appeared to be autosomal dominant with incomplete penetrance. Electron microscopy study of synovium and cartilage biopsies from one patient demonstrated calcium pyrophosphate dihydrate crystals. HLA typing revealed that all affected subjects bore the haplotype A1 B12 DR3.     

Audit of closed synovial biopsy in the diagnosis of inflammatory joint disease

In a prospective study, the clinical features and synovial histopathology of 78 patients with joint disease were compared. Nineteen patients had early rheumatoid disease, 19 chronic rheumatoid, 17 chondrocalcinosis or osteoarthritis, 10 persistent monoarthritis and 14 other miscellaneous arthropathies. After semiquantitative assessment of the degree of inflammatory infiltration, increase in vascularity, synovial hypertrophy and ulceration and fibrin deposition biopsies were categorized as either normal, or slightly or severely abnormal. The highest incidence of severely abnormal biopsy was in patients with chronic rheumatoid disease and miscellaneous forms of arthritis. Major histological abnormalities were uncommon in osteoarthritis, chondrocalcinosis and persistent monoarthritis. Generally, histology was of little help in differential diagnosis, but in early rheumatoid disease there was a relationship between the clinical degree of knee joint disease and the category of histological change. In these patients, general disease activity was reassessed at least 18 months after biopsy. All those with severely abnormal biopsies had persistent or severe persistent rheumatoid disease, whereas 3 of the 4 patients with normal biopsies had no evidence of active synovitis.     

Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia

Hemolytic anemia is a forme fruste of systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 African-American, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (alpha = 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene, SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.     

A comparison of clinical and immunogenetic features in familial and sporadic rheumatoid arthritis

Clinical and immunogenetic factors were compared in 214 patients with sporadic rheumatoid arthritis (RA) and 117 patients from 52 multiplex families. Sex distribution, articular disease severity and seropositivity for rheumatoid and antinuclear factors were similar in familial and sporadic disease. There was a trend for Sj?gren's and Felty's syndromes to be more frequent in familial RA but extraarticular disease features were otherwise similar in the 2 RA disease groups. Mean age of onset was 41.1 years in familial and 46.5 years in sporadic RA (p less than 0.0006); 67% of family probands, 74% of affected relatives and 57% of sporadic patients were HLA-DR4 positive (p less than 0.05 affected relatives vs sporadic). The similarity of clinical features found in familial and sporadic RA justifies the use of families with RA to study aspects of disease pathogenesis.     

Mitochondrial diabetes mellitus: Prevalence and clinical characterization of diabetes due to mitochondrial tRNALeU(UUR) gene mutation in Japanese patients

Summary Mutations in the mitochondrial gene were recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondrial gene is maternally inherited, Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leucocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNA^Leu(UUR) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients who were screened. Diabetes co-segregated with the mutation, except in one young subject, and was maternally inherited. The apparent onset of disease occurred between 11 and 68 years of age. Some of the affected members developed hearing impairment and congestive heart failure due to cardiomyopathy, though generally long after the onset of diabetes, and these patients had therefore not been diagnosed as having a specific form of diabetes. The duration of sulphonylurea treatment was not more than 8 years in these pedigrees and affected members were prone to progression to insulin-requiring diabetes. Thus, these patients were secondary sulphonylurea failures. Long-term follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. Some were initially diagnosed as having IDDM based on an apparent acute onset in youth and the clinical severity of their diabetes. Others were regarded as having MODY with an aggressive course. The mitochondrial gene mutation or diabetes is not transmitted to all offspring of the affected mothers. In conclusion, a mitochondrial tRNA^Leu(UUR) gene mutation accounts for slightly more than 1 % of diabetic patients with maternally inherited disease and manifests a wide range of diabetic phenotypes, from the NIDDM phenotype to IDDM, in Japanese. [Diabetologia (1994) 37: 504–510] Received: 15 September 1993 and in revised form: 3 December 1993     

Arthritis in hereditary hemochromatosis

Seven pedigrees with 45 members were evaluated for arthropathy associated with hereditary hemochromatosis (HC). Patients with symptomatic extraarticular disease were compared with asymptomatic patients who had evidence of HC on laboratory findings, and with normal subjects. Patients who were homozygous for HC were compared with heterozygous patients and normal subjects. HC arthritis does not appear to be an early predictor of disease, and chondrocalcinosis is a late manifestation of HC arthropathy.     

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.