Medullary carcinoma of the thyroid in Norway. Clinical course and endocrinological aspects

A study of the clinical, biochemical and histological findings of 57 patients with medullary thyroid carcinoma (MCT) in Norway, is presented. The diagnosis was established by light and electron microscopy and by measurements of immunoreactive calcitonin (iCT) in serum. The major factor influencing the prognosis was the extension of the disease at presentation. None of the 24 patients with tumour confined to the thyroid gland have died of the disease, and serum iCT was normal in 15 patients. Of 19 patients with regional lymph node metastes only 11 are alive 1 to 14 years after treatment, and of these 9 had increased serum iCt. 14 patients technically inoperable and/or with distant metastases, 12 have died of MCT, 1 are alive with elevated serum iCT. Of 14 patients with raised serum iCT, 8 have no clinical recurrence of the disease from 1 to 15 years after the operation. MCT-associated diseases were found in 8 patients, chronic thyroiditis in 10. Serum iCT was measured in 249 relatives of 42 patients, and abnormal elevations were found in 11 members of 6 families.     

Genetic heterogeneity of ischemic (coronary) heart disease

Results are presented on a study of the blood coagulation system and some indices of serum lipids and proteins in 133 normal individuals and probands with ischaemic heart disease and their 681 relatives. The examination of the relatives of probands with different types of biochemical disorders revealed a similar biochemical background in the probands and the members of their families. The disorders in blood biochemistry in the probands were most similar in the parents, the children of the probands' siblings, and less distinct in more distant relatives (cousins, nephews and nieces, etc.), biochemical disorders similar to those of the probands being found in young persons (14-16 years old) and reappearing in several generations. The author concludes on the genetic heterogeneity of ischaemic (coronary) heart disease and underlying coronary atherosclerosis.     

Familial occurrence of Hirschsprung's disease

We assessed the familial occurrence of Hirschsprung's disease from 224 probands born in Denmark after 1959. Probands who were still alive received a mailed questionnaire, and medical reports for the probands and their relatives with suspected Hirschsprung's disease were examined. The diagnosis of Hirschsprung's disease required a histologically verified biopsy or surgical colonic specimens, and exclusion of a secondary causes for Hirschsprung's disease. Familial occurrence was seen in 11 families. Ten first-degree, two third-degree and one fifth-degree relatives had Hirschsprung's disease. Both short segment agangliosis (the sigmoid colon or below) and long segment agangliosis (above the sigmoid colon) occurred in five of the 11 families, implying that the etiology of Hirschsprung's disease with short and long segment agangliosis is the same. Compared with the general population, the first-degree relatives of the 224 probands had a minimum of a 93-fold increased risk of Hirschsprung's disease. This strongly suggests that genetic factors play a role in Hirschsprung's disease.     

Idiopathic dilated cardiomyopathy: familial prevalence and HLA distribution

OBJECTIVES: To compare HLA distribution in familial and non-familial dilated cardiomyopathy, because a serum marker that could identify families at risk of developing dilated cardiomyopathy should be of use in screening for the disease. PATIENTS: 100 patients with dilated cardiomyopathy. METHODS: 200 first degree relatives from 56 of the proband families were screened for dilated cardiomyopathy by echocardiography. The HLA profile of the patients with dilated cardiomyopathy, as well as of the familial and non-familial subgroups, was compared with that of 9000 normal controls. RESULTS: The familial prevalence of dilated cardiomyopathy in this patient group was "definite" in 14 of 56 (25%) and "possible" in 25 of 56 (45%). The HLA-DR4 frequency in the 100 patients with dilated cardiomyopathy was similar to that in the 9000 controls (39% v 32%). However, the DR4 subtype was significantly more common in the 25 probands with a familial tendency to dilated cardiomyopathy than in the 31 probands with non-familial dilated cardiomyopathy (68% v 32%; P < 0.05). CONCLUSIONS: The present finding supports an HLA linked predisposition to familial dilated cardiomyopathy. The HLA type DR4 was significantly more common in familial than in non-familial cases. The DR4 halotype was associated with two thirds of the families at risk for dilated cardiomyopathy.     

A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2

Familial nonmedullary thyroid cancer (FNMTC) is a clinical entity characterized by a phenotype more aggressive than that of its sporadic counterpart. Families with recurrence of nonmedullary thyroid cancer (NMTC) have been repeatedly reported in the literature, and epidemiological data show a very high relative risk for first-degree relatives of probands with thyroid cancer. The transmission of susceptibility to FNMTC is compatible with autosomal dominant inheritance with reduced penetrance, or with complex inheritance. Cases of benign thyroid disease are often found in FNMTC kindreds. We report both the identification of a new entity of FNMTC and the mapping of the responsible gene, named "TCO" (thyroid tumors with cell oxyphilia), in a French pedigree with multiple cases of multinodular goiter and NMTC. TCO was mapped to chromosome 19p13.2 by linkage analysis with a whole-genome panel of microsatellite markers. Interestingly, both the benign and malignant thyroid tumors in this family exhibit some extent of cell oxyphilia, which, until now, had not been described in the FNMTC. These findings suggest that the relatives of patients affected with sporadic NMTC with cell oxyphilia should be carefully investigated.     

Biochemical composition of human peripheral arteries examined with near-infrared Raman spectroscopy

OBJECTIVE: To describe the clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy (IIM) and to compare these with the features of sporadic IIM. METHODS: Clinical signs and symptoms, autoantibodies, HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected and 28 unaffected members of 16 unrelated families in which 2 or more blood relatives developed an IIM. In addition, findings in patients with familial IIM were compared with those in 181 patients with sporadic IIM. The families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other siblings or relatives with polymyositis or dermatomyositis, and 2 families with inclusion body myositis. RESULTS: The clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies was lower in familial than in sporadic IIM. DRB1*0301 was a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic IIM). Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P = 0.002). CONCLUSION: These findings emphasize that 1) familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and 2) multiple genetic factors are likely important in the etiology and disease expression of familial IIM, as is also the case for sporadic myositis, but DQA1 homozygosity is a distinct risk factor for familial IIM.     

Increased risk for type I (insulin-dependent) diabetes in relatives of patients with alopecia areata (AA)

The prevalence of various chronic diseases was compared in 517 individuals with alopecia areata, and 2,969 of their first degree relatives. As previous reports have suggested an increased incidence of diabetes in relatives of patients with alopecia areata, special attention was given to the prevalence of Type 1 and Type 2 diabetes in the patients and in their relatives. Several immunologic diseases were increased in alopecia probands and relatives. Thyroid disease, vitiligo, Addison disease, and pernicious anemia were more prevalent in probands and in their relatives than in the general population. Specifically, a high rate of thyroid disease was found in probands (14.7%) and in their first degree relatives (4.2%). Only one proband had Type 1 diabetes, yet there were 14 sibs with Type 1 diabetes. Thus, Type 1 diabetes was significantly more prevalent in the sibs (1.2%) than in either the probands with alopecia (0.2%), or the general population (0.12-0.25%) (P < 0.05)). In contrast, Type 2 diabetes was not more common in probands or in sibs than in the general population. These data suggest that alopecia areata protects against Type 1 diabetes in predisposed individuals. The high rate of thyroid disease suggests that screening probands and first degree relatives for thyroid disease should be considered.     

Nucleic acid technology (NAT) testing and the transfusion service: a rationale for the implementation of minipool testing

Breast cancer is the single largest cancer and causes the high rate of cancer mortality among women. A positive family history of breast cancer is recognized as one of the major risk factors for this disease. The present study evaluates bleomycin (BLM)-induced chromosome sensitivity analysis in breast cancer families which provides indirectly a measure of the DNA repair defect of each person. BLM sensitivity assay on cultured lymphocytes of 36 familial breast cancer patients, their 85 first or second degree female relatives, 36 sporadic breast cancer patients and 40 age- and sex-matched controls (without any family history of cancer) were carried out to measure interindividual variation in their DNA repair capacity through mutagen-induced chromosome sensitivity analysis. Fifty percent of familial breast cancer patients and seven unaffected relatives showed hypersensitivity. Compared to hyposensitive relatives these seven subjects may be considered as high risk individuals.     

Familial aggregation of primary Raynaud's disease

OBJECTIVE: To determine the occurrence of familial aggregation of primary Raynaud's disease. METHODS: Twenty-three patients with primary Raynaud's disease and their first-degree relatives were assessed by questionnaire and, when possible, by physical examination. The same procedures were performed on the patients' spouses and the spouses' first-degree relatives, who served as the control group. RESULTS: The prevalence of Raynaud's disease was significantly higher in the families of the probands than in the control families when assessed by questionnaire (26.1% versus 5.5%; P < 10(-5)), and by physical examination (11.2% versus 2.8%; P = 0.015). CONCLUSION: These findings demonstrate that there is significant familial aggregation of primary Raynaud's disease.     

Oncological implications of RET gene mutations in Hirschsprung's disease

BACKGROUND: Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschsprung's disease. Some patients with Hirschsprung's disease may therefore be exposed to a highly increased risk of tumours. AIMS: To define clinical use of RET gene testing in Hirschsprung's disease and related patient management from an oncological point of view. METHODS: Sixty patients with Hirschsprung's disease were screened for RET mutations. In three, MEN2A type RET mutations were detected. Case reports for these three patients are presented. RESULTS AND CONCLUSIONS: Only 22 families or sporadic patients with Hirschsprung's disease and MEN2A type RET mutations have been reported. Therefore, it is difficult to predict tumour risk for patients with familial or sporadic Hirschsprung's disease, and their relatives, who carry these mutations. For these mutation carriers, periodic screening for tumours as in MEN2A is advised, but prophylactic thyroidectomy is offered hesitantly. RET gene testing in familial or sporadic Hirschsprung's disease is not recommended at present outside a complete clinical research setting. In combined MEN2A/Hirschsprung's disease families RET gene testing, tumour screening, and prophylactic thyroidectomy are indicated as in MEN2A.     

Genetics of ischaemic heart disease

Coronary heart disease, especially when it affects younger individuals, tends to cluster in families. Known risk factors occur in 50-75% of patients with myocardial infarction. Yet commonly occurring risk factors are not strongly inherited, and the familial aggregation of coronary heart diseas may not be attributable to familial resemblance in serum cholesterol and blood pressure levels. Alternatively, such aggregation may be due to unknown familial risk factors. Nevertheless, screening of relatives of individuals with evident risk factors is of importance, and environmental manipulation is likely to be of value in prevention of coronary heart disease.     

Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity?

Although the prevalence of asthma has risen significantly during the last 30 yr, it is not clear whether this has occurred primarily in persons with a strong genetic predisposition to asthma and atopy or in other sections of the population. We have investigated outcomes in children of nuclear families selected through probands previously characterized by studies in 1964 and 1989 as having histories of persistent childhood onset atopic asthma, transient childhood wheezy bronchitis, and no respiratory symptoms or atopy. Children of wheezy bronchitic probands had a significantly better symptomatic outcome in adolescence, irrespective of the atopic status of the parent proband, than do children of either asthmatic or asymptomatic probands, suggesting that this may be a syndrome that shows familial aggregation and is distinct from asthma. Total serum IgE levels were significantly lower in children of nonatopic asymptomatic probands, including those with wheezing symptoms. In contrast children of nonatopic asymptomatic probands had an unexpectedly high prevalence of wheezing (33%), positive skin prick tests (56%), and positive specific serum IgE to common allergens (48%) that was similar to that found in children of atopic asthmatic probands. Our findings support the concept that wheezy bronchitis is a separate syndrome from atopic asthma. High total serum IgE levels within our population appear to be an important marker of genetic predisposition to atopy. Our data also suggest that much of the increase in asthma prevalence is associated with specific IgE sensitization and is occurring in persons previously considered to be at low risk of developing asthma or atopy.     

The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies

BACKGROUND: Although replication is the heart of science, psychiatric geneticists rarely have the opportunity to replicate findings, especially more than once. METHODS: This article reviews results from three independent family studies of schizophrenia on which one of us conducted diagnostic reviews: the Danish Adoption Study (DAS), the Iowa 500 non-500 family study (IFS), and the Roscommon Family Study (RFS). We utilized DSM-III or DSM-III-R criteria and meta-analysis techniques. RESULTS: The odds ratios (OR) in personally interviewed, first degree biological relatives of schizophrenic and matched control probands for schizophrenia, other non-affective psychoses (ONAP), schizotypal personality disorder (SPD), unipolar affective illness (UPAI), bipolar affective illness (BPAI), and anxiety disorders were homogeneous across studies. For alcoholism, ORs were significantly heterogeneous. Schizophrenia, SPD and ONAP strongly aggregated in relatives of schizophrenic probands with decreasing common OR estimates of 16.2, 5.0 and 4.0, respectively. The common OR for anxiety disorders was 1.1, indicating no familial co-aggregation. For UPAI and BPAI, the common ORs exceeded unity (1.3 and 1.9, respectively), although only the former was statistically significant. CONCLUSIONS: Schizophrenia strongly aggregates in families and shares familial factors with SPD and ONAP but not anxiety disorders. The familial factors of aetiological importance for schizophrenia and affective illness may be weakly related. With the exception of alcoholism, the patterns of psychiatric disorders in relatives of schizophrenic and control probands in these three studies were sufficiently similar that, despite their methodological differences, they can probably be viewed as replications of one another.     

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.     

Co-morbidity and familial aggregation of alcoholism and anxiety disorders

BACKGROUND: This study examined the patterns of familial aggregation and co-morbidity of alcoholism and anxiety disorders in the relatives of 165 probands selected for alcoholism and/or anxiety disorders compared to those of 61 unaffected controls. METHODS: Probands were either selected from treatment settings or at random from the community. DSM-III-R diagnoses were obtained for all probands and their 1053 first-degree relatives, based on direct interview or family history information. RESULTS: The findings indicate that: (1) alcoholism was associated with anxiety disorders in the relatives, particularly among females; (2) both alcoholism and anxiety disorders were highly familial; (3) the familial aggregation of alcoholism was attributable to alcohol dependence rather than to alcohol abuse, particularly among male relatives; and (4) the the pattern of co-aggregation of alcohol dependence and anxiety disorders in families differed according to the subtype of anxiety disorder; there was evidence of a partly shared diathesis underlying panic and alcoholism, whereas social phobia and alcoholism tended to aggregate independently. CONCLUSIONS: The finding that the onset of social phobia tended to precede that of alcoholism, when taken together with the independence of familial aggregation of social phobia and alcoholism support a self-medication hypothesis as the explanation for the co-occurrence of social phobia and alcoholism. In contrast, the lack of a systematic pattern in the order of onset of panic and alcoholism among subjects with both disorders as well as evidence for shared underlying familial risk factors suggests that co-morbidity between panic disorder and alcoholism is not a consequence of self-medication of panic symptoms. The results of this study emphasize the importance of examining co-morbid disorders and subtypes thereof in identifying sources of heterogeneity in the pathogenesis of alcoholism.     

Segregation analysis of breast cancer in a population-based sample of postmenopausal probands: The Iowa Women's Health Study

Inheritance of a major susceptibility gene for breast cancer has been primarily investigated in families with early-onset disease. However, familial clustering of late-onset breast cancer is well documented, and genetic factors may also be relevant. In the Iowa Women's Health Study, we evaluated evidence for a major gene after allowing for measured environmental risk factors. Two hundred sixty-five incident breast cancer probands were identified from a prospective cohort study of 41,837 women aged 55 to 69 years at baseline in 1986. A pedigree development form was mailed to the probands to ascertain all first-degree female relatives. A questionnaire and body measurement protocol were mailed to identified living relatives or surrogates. Segregation analyses were conducted on a total of 1,145 women in 251 families using regressive models as implemented in S.A.G.E. Mendelian codominant inheritance of an allele that produced an earlier-age-at-onset provided the best fit to the data. Incorporation of measured environmental risk factors as covariates yielded no significant improvements in the likelihoods. Approximately 50% of this population could be expected to carry a late-onset breast cancer susceptibility gene, and 23% of the population is susceptible because of the environment in which they live. Homozygous gene carriers are predicted to have a mean age-at-onset of 48 years, over 20 years earlier than heterozygotes; few cases would be expected among non-gene carriers. In conclusion, the transmission pattern of late-onset breast cancer may be determined by a common susceptibility gene.     

Familial subtypes of attention deficit hyperactivity disorder: a 4-year follow-up study of children from antisocial-ADHD families

ADHD is a familial disorder with high rates of comorbidity with conduct disorder in childhood and antisocial personality and substance use disorders in adulthood. A growing literature suggests that ADHD with antisocial comorbidity may be nosologically distinct from other forms of ADHD. Previously, we proposed a family-based stratification that defined Antisocial families as those with either conduct disorder or antisocial personality disorder in the probands or relatives. To provide predictive validity for that stratification, we assessed psychopathology in these families 4 years after their initial assessment. Results show that the probands and siblings from Antisocial families had higher rates of psychopathology during the 4-year follow-up period compared with siblings from Non-antisocial and control families. They also had more deviant ratings on the Child Behavior Checklist (especially for anxious/depressed, delinquent, and aggressive behavior). We found fewer group differences in the academic, psychosocial, and intellectual correlates of ADHD. These results confirm and extend previous work indicating that Antisocial ADHD may be a nosologically and clinically meaningful subform of ADHD.     

Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews

The Jewish population has an increased frequency of inflammatory bowel disease compared with their non-Jewish neighbours. Genetic factors have been implicated in the aetiology of this disorder and may contribute to ethnic differences. This study determined the familial empirical risks for inflammatory bowel disease in the first degree relatives of inflammatory bowel disease probands (for both Jews and non-Jews) for the purpose of accurate genetic counselling and genetic analysis. A total of 527 inflammatory bowel disease patients from Southern California (291 Jews and 236 non-Jews) were questioned about inflammatory bowel disease in their first degree relatives (a total of 2493 individuals). Since inflammatory bowel disease has a variable and late age of onset, age specific incidence data were used to estimate the life time risks and to make valid comparisons between the different groups. In the first degree relatives of non-Jewish probands, the life time risks for inflammatory bowel disease were 5.2% and 1.6% when probands had Crohn's disease and ulcerative colitis respectively. These values were consistently lower than the corresponding risks for relatives of Jewish patients -7.8% and 4.5% for Crohn's disease and ulcerative colitis probands respectively (p value for comparison between Jews and non-Jews: 0.028; between ulcerative colitis and Crohn's disease: 0.005). These data provide the requisite basis for genetic counselling for these disorders in the white American population. In addition, these different empirical risks for relatives of Jewish and non-Jewish probands allow rejection of single Mendelian gene models for inflammatory bowel disease, but are consistent with several alternative genetic models.     

Smooth-pursuit eye movement dysfunction and liability for schizophrenia: Implications for genetic modeling.

41 nonpsychiatric Ss, 38 probands with schizophrenia, and 99 of their relatives were studied. Oculomotor functioning was bimodally distributed for probands and relatives. Oculomotor dysfunction was not present in all families with a schizophrenic proband. In those families in which it was present, there were significant phenotypic correlations between oculomotor functioning and schizophrenia-related characteristics. The patterns of familial resemblance in the families in whom oculomotor dysfunction was present were consistent with nonadditive genetic variance contributing both to oculomotor dysfunction and to the relationship between oculomotor dysfunction and clinical symptoms. These results suggest that schizophrenia may be etiologically heterogeneous and that oculomotor dysfunction may help to identify nonadditive genetic variance for this disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interferon-gamma-activated monocytes impair infectivity of HIV particles by an oxygen metabolite-dependent reaction

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications and diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. Previously published blood cholesterol criteria greatly underdiagnosed new cases of FH among members of known families with FH in Utah and overdiagnosed FH among participants of general population screening, revealing the need for different cholesterol screening criteria in persons from these 2 different settings. The statistical concept of a priori probabilities was applied to derive 2 sets of practical screening criteria: one for persons participating in general population screening studies and another for close relatives of confirmed FH cases, showing dramatic differences. At a cholesterol level of 310 mg/dl, only 4% of persons in the general population would have FH but 95% of persons who were first-degree relatives of known cases would have FH. Detailed tables were derived to provide practical total and low-density lipoprotein blood cholesterol screening criteria for diagnosing FH in different screening settings and specific age groups. In population screening the new FH criteria require a total cholesterol > 360 mg/dl for age 40+ (or 270 mg/dl in youth). Among first-degree relatives of confirmed cases in families with FH, the new total cholesterol criteria are much lower (> 290 mg/dl for age 40+, > 220 mg/dl for youth).(ABSTRACT TRUNCATED AT 250 WORDS)