Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease

Eighty-seven patients diagnosed as having primary Raynaud's phenomenon (Raynaud's disease) were reexamined after this symptom had been present for a mean of 8.8 years (range 2.0-34.5). One or more additional clinical feature(s) suggesting an underlying connective tissue disease were found in 12 patients (14%) at first evaluation, and in 23 (26%) by the last evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients), and digital tip ulcerations (6 patients). Distal esophageal hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients. Only 4 individuals (5%) developed clear evidence of a connective tissue disease, and in all cases, the diagnosis was the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome variant of systemic sclerosis. This condition became obvious 8-17 years after the onset of Raynaud's phenomenon. One or more serologic test values were initially abnormal in 2 of these CREST syndrome patients, as well as in 12 patients who continued to have primary Raynaud's phenomenon at the last evaluation. The combination of puffy fingers, digital pitting scars, and serum anticentromere antibody, all consistent with CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were repeated during followup had a change in the serologic profile. These results suggest that only a small proportion of patients with primary Raynaud's phenomenon develop one of the connective tissue diseases during the first decade after onset. When such a disorder does appear, systemic sclerosis with the CREST syndrome variant is the most likely eventual diagnosis.     

Familial aggregation of low-renin hypertension

Low-renin hypertension, representing roughly one quarter of all essential hypertension, is widely recognized by distinct physiological features, including salt-sensitivity, diuretic- responsiveness, and a favorable natural history. Although certain demographic features including age, ethnicity, and diabetes mellitus predispose to low-renin hypertension, these factors account for only a minority of cases. We examined familial concordance for renin status in 119 families with 257 hypertensive members. Low-renin was defined rigorously by plasma renin activity < or =0.69 ng angiotensin I/L per second, drawn when subjects had achieved balance after 5 to 7 days on a 10 mmol sodium diet and had stood upright for at least 1 hour. Given the prevalence of low-renin hypertension in our general population, low-renin hypertension was significantly more concordant among siblings than expected by chance (P=0.01). There were twice as many low-renin families as expected (10.9% versus 5.5%), in sharp contrast to the normal-renin state, in which the observed and expected were similar (61.0% versus 58.6%). These results were independent of age, race, and gender. Variance in renin status attributable to family membership was 35%. Association studies were performed on 8 polymorphisms in 5 candidate genes, and significant association was confirmed with the G460W polymorphism of the adducin gene. Familial determinants, which are probably but not definitely genetic, contribute to the low-renin hypertension state.     

强直性脊柱炎家族聚集性研究

目的 通过强直性脊柱炎(AS)病例的家族发病情况调查及一级亲属人类白细胞抗原(HLA)-B27检测，得出本区域强直性脊柱炎家族发病情况及有关遗传方式，一级亲属再显风险率和遗传率评估等资料。方法 采用问卷调查形式，记录本人及一级亲属中有关脊柱关节病的相关症状。收到有效回复248例。其中47例亲属有症状，并持续3个月以上。约来院复查，详细询问病史并行体检，留取血样本，根据病情预约双侧骶髂关节位放射学检查，确定能否诊断AS。并分别计算一级亲属再显风险率及遗传率。所有患者和部分一级亲属采用流式细胞仪测定HLA-B27。并对100例正常献血者行HLA—B27检查。结果 248例AS家族中有第2例AS的先证者共38例。AS患者亲属确诊AS共有43例，其中一级亲属患AS30例。AS先证者一级亲属再显风险率为15．7％，其中同胞再显风险率是7．33％。推算一般AS家庭一级亲属再显风险率为2．4％。根据1998年我科在五角场地区流行病学调查，本地区AS群体发病率是0．11％，本组AS先证者一级亲属的过度危险性为142．7，先证者家庭同胞的过度危险性为66．6，一般AS家庭过度危险性为21．8。计算AS遗传率为71％。预期一级亲属发病率为3．3％，与实际得出的3．0％基本一致。与亲属AS比较，先证者中女性患者比例明显升高(达34．2％)，发病年龄相对较轻，病情较轻者少(P≤0．05)。对AS患者一级亲属行HLA—B27检查，阳性率为63％。无任何症状的一级亲属HLA—B27阳性率仍高达55％。AS在一级亲属中的确诊率28％，分别占一级亲属中HLA—B27阳性和有症状者的45％。与本地区正常献血者HLA—B27阳性率5％相比较，差异均有非常显著性(P≤0．01)。结论 AS是有较高家族聚集性的多基因遗传性疾病，HLA-B27在AS家族中有很高的阳性率。应高度重视AS家庭背景的分析。     

Familial aggregation of blood pressure

Familial aggregation of blood pressure (BP) was studied in 545 families, of which 370 included natural children only, 24 adopted children only and 175 both natural and adopted children. Mean values of four Automatic BP measurements (Dinamap 845) were converted into age (adult) or height (children) and sex adjusted scores. One comparison per family between parents and randomly chosen index children were made. A significant resemblance of blood pressure is observed between natural children and their parents: Systolic BP r = 0.24. Diastolic BP r = 0.29. N = 272 p less than 0.05. Adopted children did not have BP resemblances to the mean BP values of their parents but a significant resemblance was found between children and their mothers for a small sample (N = 46). Weight, heart rate, age and duration of cohabitation do not influence the results. A familial influence on BP can be detected in children. However, estimating the relative contribution of genetic and common environmental factors to BP correlations between family members is difficult. Nevertheless, the BP of children whose parents have high BP should be monitored.     

Familial dysalbuminemic hyperthyroxinemia associated with primary thyroid disease

This study describes a family with intrinsic thyroid disease in addition to familial dysalbuminemic hyperthyroxinemia, a syndrome associated with euthyroidism and increased binding of thyroxine to serum albumin. The simultaneous occurrence of thyroid disease and elevated serum thyroxine concentrations due to familial dysalbuminemic hyperthyroxinemia may confound the diagnosis of the two concurrent disorders and the subsequent therapy of the thyroid disease.     

Mechanisms of Raynaud's disease

Raynaud's phenomenon is due to transient cessation of blood flow to the digits of the hands or feet. An attack of Raynaud's phenomenon is classically manifested as triphasic color changes. The white phase is due to excessive vasoconstriction and cessation of regional blood flow. This phase is followed by a cyanotic phase, as the residual blood in the finger desaturates. The red phase is due to hyperemia as the attack subsides and blood flow is restored. An attack is frequently associated with pain and/or paresthesia due to sensory nerve ischemia. Variants of Raynaud's phenomenon include acrocyanosis and primary livedo reticularis, each of which is associated with reduced skin blood flow, exacerbated by cold or emotional upset. Raynaud's phenomenon in the absence of other disorders is primary Raynaud's phenomenon, or Raynaud's disease. The mechanisms of Raynaud's disease include increased activation of the sympathetic nerves, in response to cold or emotion; an impaired habituation of the cardiovascular response to stress may contribute. In addition, there appears to be a local fault, which is likely multifactorial. This local fault is due to an alteration in vascular function rather than vascular structure. The alteration in vascular function may be related to increased sensitivity to cold of the adrenergic receptors on the digital artery vascular smooth muscle. In some cases, locally released or systemically circulating vasoconstrictors may participate, including endothelin, 5-hydroxytryptamine and thromboxane. A deficiency or increased degradation of nitric oxide, possibly due to increased oxidative stress, may be involved in some cases. These recent pathophysiological insights may lead to new therapeutic options.     

Familial aggregation of juvenile idiopathic arthritis

OBJECTIVE: To estimate the degree of familial aggregation of juvenile idiopathic arthritis (JIA), determine whether the aggregation of JIA and the aggregation of type 1 diabetes mellitus (type 1 DM) overlap, and identify multiplex JIA pedigrees. METHODS: Records of individuals with JIA or type 1 DM were probabilistically linked with records in the Utah Population Database (UPDB), a large computerized family history database. For each case of JIA or type 1 DM, 10 matched controls or 5 matched controls, respectively, were selected. All familial relationships among cases of JIA or type 1 DM were established. A familial risk score was calculated for each subject. For various levels of familial exposure to JIA or type 1 DM, one's risk (odds ratio [OR]) of developing JIA or type 1 DM was established (cases compared with controls). Recurrence risks for JIA were computed for relatives of JIA cases compared with relatives of controls. Extended JIA families were identified from a list of common ancestors. RESULTS: Records of a total of 443 patients were linked with the UPDB. Of these, 381 (86.0%) met criteria for JIA. An increased risk for JIA was observed among relatives of probands with JIA. The prevalence of type 1 DM among JIA cases was higher than the US prevalence of type 1 DM (P < 0.003). The recurrence risk for JIA was significantly elevated among first-degree relatives of cases with JIA (OR 30.4). The overall prevalence of JIA was 28/100,000. Four extended JIA pedigrees were identified. CONCLUSION: There is familial aggregation of JIA in the Intermountain West region of the US. We have demonstrated that multiplex JIA pedigrees can be identified using a genealogic database.     

Familial disturbance of fibrin monomer aggregation

The investigation of the cause of an accidentally observed prolonged prothrombin time in a patient without a haemorrhagic diathesis led to the discovery of a familial disturbance of the aggregation of fibrin monomers (von Felten, Duckert and Frick, 1965). The observed defect differs from previously reported anomalies in the last phase of coagulation such as congenital afibrinogenaemia or hypofibrinogenaemia (Frick and McQuarrie, 1954), congenital fibrin-stabilizing-factor (FSF) deficiency (Duckert, Jung and Shmerling, 1960), and congenital dysfibrinogenaemia (Beck, 1964). It may be similar to the fibrinogen anomaly described by Ménaché (1963).     

Familial aggregation of early-onset myocardial infarction

BackgroundAn inherited predisposition is an important factor in the etiology of myocardial infarction (MI) at a young age. However, the extent of the risk for early-onset MI in relatives of young patients is still unclear, due to the paucity of family history data. Hence familial aggregation of early-onset MI was investigated in a cohort of relatives of Italian patients who had survived MI who occurred at the age of 45 or earlier.MethodsIn the framework of a case–control study, lifetime data and early-onset MI status for 11,696 relatives of cases and 8897 relatives of controls were collected using a standardized questionnaire.ResultsOccurrence of early-onset MI in females was very uncommon (Kaplan–Meier risk = 0.6%, 95% confidence interval (CI): 0.38–0.82%, for female case relatives), and significantly lower than that for male case relatives (5.0%, 95% CI: 4.41–5.56%). The hazard ratio (HR) for case relatives was approximately 3-fold greater than that for control aunts (taken as reference category). Risk for early-onset MI to siblings (HR = 1.7, 95% CI: 1.33–2.18) was significantly different from that to parents (HR = 0.9, 95% CI: 0.71–1.16). The familial risk ratio λ_R was 2.6 (95% CI: 2.30–2.89) for case relatives, using control parents as reference population for early-onset MI risk estimates (i.e. 37 per 100,000 in fathers and 7 per 100,000 in mothers).ConclusionWe evaluated the risk of early-onset MI by category of relatives, obtaining evidence for familial aggregation of the disease in this Italian sample and providing figures for genetic counselling and planning genetic epidemiological studies.     

A double blind randomised placebo controlled trial of hexopal in primary Raynaud's disease

Summary The peripheral vasospastic symptoms associated with Raynaud's disease continue to be an unsolved clinical problem. Hexopal (Hexanicotinate inositol) has shown promise in uncontrolled studies and its use in patients with Raynaud's disease may reduce such vasospasm. This study examines the effects of 4 g/day of Hexopal or placebo, during cold weather, in 23 patients with primary Raynaud's disease. The Hexopal group felt subjectively better and had demonstrably shorter and fewer attacks of vasospasm during the trial period. Serum biochemistry and rheology was not significantly different between the two groups. Although the mechanism of action remains unclear Hexopal is safe and is effective in reducing the vasospasm of primary Raynaud's disease during the winter months.