The KIT gene in familial mastocytosis

Familial cutaneous mastocytosis is an exceptional condition of unknown etiology. In this study we report the largest series of patients with familial cutaneous mastocytosis without other manifestations (18 affected subjects from seven unrelated families), and we investigate the role of germ-line KIT mutations in the pathogenesis of the disease. The mean age at onset was 5.4 years (range from birth to 22 years), and the clinical behavior was variable over a mean follow up period of 15.1 years (range 2-36): improvement in seven, stability in eight and worsening in the remaining three patients. The pattern of inheritance was compatible with an autosomal dominant trait with incomplete penetrance; a female preponderance (14 females vs 4 males, ratio 3.5:1) was noted; among the six women who have been pregnant at least once, three experienced important clinical changes during pregnancy. No germ-line mutation was found in the exons 10, 11, and 17 of the KIT proto-oncogene, which are the most commonly mutated exons in sporadic mastocytosis. However, in the majority of affected subjects we found the Met541Leu polymorphic variant of the KIT gene, which seems to confer a growth advantage to mast cells in vitro. This observation further suggests that the Met541Leu may be a predisposing factor of cutaneous mastocytosis, although it seems to be neither necessary nor sufficient for the development of the disease.

Multiple small "imaging" branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?

Most screening programs for familial pancreatic cancer are currently based on endoscopic ultrasonography and/or magnetic resonance imaging (MRI). Cystic lesions, especially those suspicious for small intraductal pancreatic mucinous neoplasms (IPMNs) of the branch ducts, can be visualized in up to 40 % of individuals at risk, but their pathological importance in the setting of FPC is yet not well established. Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN) who underwent pancreatic resection were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Five of 125 individuals at risk who underwent screening had multiple small (size 2-10 mm) unicystic lesions and/or multicystic single lesions in the pancreatic body and tail suspicious for BD-IPMNs upon MRI imaging and decided to undergo surgical resection after interdisciplinary counselling, although none fulfilled the consensus criteria for IPMN resection. Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 4 individuals. The remaining patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN 2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Intriguingly, the location of the most dysplastic histological lesions (PanIN3) did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. In the setting of FPC, the presence of multiple small "imaging" BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas.

Fatal myocardial infarction at 4.5 years in a case of homozygous familial hypercholesterolaemia

Management of homozygous familial hypercholesterolaemia is notoriously difficult. For these patients, LDL apheresis is considered the treatment of choice. Treatment initiation is advocated generally from the age of seven years onwards (Thompson et al., Atherosclerosis 198:247-255, 2008). Here, we present the case of a young girl from a large inbred family of Turkish descent with homozygous familial hypercholesterolaemia and fatal outcome at the early age of 4(1/2) years.In conclusion, this case suggests that management of homozygous familial hypercholesterolaemia may require earlier and more aggressive treatment, including LDL apheresis before the age of seven years.

Towards a Variety of Family Models: Economic Contributions of Spouses and Family Power

In Western societies the increase in female employment (especially among married women) is seen as having brought about the crisis of the traditional model of the family, reinforcing the position of the "modern" model - the egalitarian family with two working spouses and a "dual-career" family. In contrast, the transitional situation in the post-communist countries during the 1990s is producing a crisis of the family with two working spouses (the basic type of the communist period) and leading to new power relations within the family. While the growth of dual-earner households in this century has implied modification of family models towards greater symmetry of responsibility for breadwinning and homemaking, there is considerable evidence that women's increased employment does not necessarily lead to a more egalitarian approach to gender roles within the family. The group set out to investigate the economic situation of families and economic power within the fame as a crucial factor in the transformation of families with two working spouses in order to reveal the specific patterns of gender contracts and power relations within the family that are emerging in response to the current political and economic transformation. They opted for a comparative approach, selecting the Czech Republic as a country where the very similar tendencies of a few years ago (almost 100% of women employed and the family as a realm of considerable private freedom where both women's and men's gender identities and the traditional distribution of family responsibilities were largely preserved) are combined with a very different experience in terms of economic inequalities during the 1990s to that of Russia. In the first stage of the study they surveyed 300 married couples (150 in each country) on the question of breadwinning. They then carried out in-depth interviews with 10 couples from each country (selected from among the educated layers of the population), focusing on the process of the social construction of gender, using breadwinning and homemaking as gender boundaries which distinguish men from women. By analysing changes in social position and the type of interpersonal interaction of spouses they distinguished two main types of family contracts: the neo-traditional "communal sharing" (with male breadwinner, traditional distribution of family chores and negotiated family power) and the modern one based on negotiated agreement. The most important pre-conditions of husband-wife agreement about breadwinning seemed to imply their overall gender ideology rather than the economic and/or family circumstances. In general, wives were more likely to express egalitarian views, supporting the blurring or even elimination of many gender boundaries. Husbands, on the other hand, more often gave responses calling for the continued maintenance of gender boundaries. The analysis showed that breadwinning is still an important gender boundary in these cultures, one that is assumed unless it is explicitly questioned and that is seen as part of what makes a man a "real man". The majority of respondents seemed to be committed to egalitarian ideology on gender roles and the distribution of family tasks, including decision making, but this is contradicted by the persistent idea of the husband as the breadwinner. This contradiction is more characteristic of the Russian situation than of the Czech. The quantitative study showed a difference in prevailing family models between the two countries, with a clearer shift towards the traditional family contract in the Russian case. The Czechs were more likely to consider their partnerships as based on negotiated agreement, while the Russians saw theirs as based on egalitarian contract, in both cases seeing this as the norm. The majority of couples said they felt satisfied with their marriage, although in both countries wives seemed to be less satisfied. There was however a difference in the issues that aroused dissatisfaction, with Czech women being more sensitive to issues such as self-realisation, personal independence, understanding and recognition in the family, and Russians to issues of love, understanding and recognition. The most disputed area for the majority of families was chores in the home, presumably because in many families both husband and wife were working hard outside the home and because a number of partners had differing views as to the ideal distribution of chores within the family. The distribution of power in the family seems to be linked to the level of well being. The analysis showed that in the dominant democratic model there is still an inverse connection between family leadership and well being: the more prominent the wife's position as head of the family is, the lower the level of family income. This may reflect both the husband's refusal to play the leading role in the family and even his rejection of any involvement in family issues in such a family. The qualitative research revealed that both men and women see the breadwinning role to be an essential part of masculine identity, a role which the female partner would take on temporarily to assist the male but not permanently since this would threaten the gender boundaries and the man's identity. At the same time, few breadwinners expressed a sense of job satisfaction and all considered their choice as imposed on them by the circumstances (i.e. having a family in difficult times). The group feel that family orientation and some loss of personal involvement in their profession is partly reflected in the fact that many of the men felt more comfortable and self-confident at home than at work. Women's work, on the other hand, was largely seen as a source of personal and self-realisation and social life. Eight out of ten of the Russian women interviewed were employed, although only two on a full-time basis, but none saw their jobs as adding substantially to the family budget. Both partners see the most important factor as the wife's wish to work or stay at home, and do not think it wise for the wife to work at the expense of her part of the "family contract", although husbands from the "egalitarian" relationships expressed more willingness to compromise. The analysis showed clearly that wives and husbands did not construct gender boundaries in isolation, with the interviews providing clear evidence of negotiation. At the same time, husbands' interpretations of their wives' employment were less susceptible to the influence of negotiation than were their gender attitudes and norms about breadwinning. One of the most interesting aspects of the spouses' negotiations was the extent to which they disagreed about what they seemed to have agreed upon. Most disagreements about the breadwinning boundaries, however, were over norms and were settled by changes in norms rather than in behavioural interpretation. Changes in norms were often a form of peace offering or were in response in changes in circumstances. The study did show, however, that many of the efforts at cooperation and compensation were more symbolic than real and the group found the plasticity of expressed gender ideology to be one of the most striking findings of their work. They conclude that the shift towards more traditional gednder distributions of incomes and domestic chores does not automatically mean the reestablishment of a patriarchal model of family power. On the contrary, it seems to be a compromise formation, relatively unstable, temporary and containing self-defeating forces as the split between the personal and professional value of work and its social value expressed in a money equivalent cannot be maintained for generations.

Recurrent acute and chronic pancreatitis in two brothers with familial chylomicronemia syndrome

The chylomicronemia syndrome is well recognized as a rare etiologic factor of acute pancreatitis; however, whether hypertriglyceridemia can cause chronic pancreatitis (CP) remains unclear. We describe the long-time course of 2 brothers with the familial chylomicronemia syndrome caused by identical compound heterozygous mutations in the lipoprotein lipase (LPL) gene with markedly reduced LPL activity. Other etiologic factors were excluded, including mutations in the PRSS1, SPINK1, and CFTR gene. Although both brothers had recurrent acute pancreatitis and the same LPL genotype, CP became evident in only one patient. Progression to CP was associated with a more severe disease course. Thus, the chylomicronemia syndrome may cause CP in the absence of other known causative factors, and similar to alcoholic and hereditary CP, a more severe disease course is associated with disease progression.

Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia

PURPOSE: The transcription factor CCAAT/enhancer binding protein-alpha (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known. PATIENTS AND METHODS: In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients. RESULTS: We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient. CONCLUSION: This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease.

Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation

The S218L CACNA1A mutation has been previously described in two families with familial hemiplegic migraine. We present three siblings with the mutation with the novel association of childhood seizures, and highlight the dynamic changes seen on electroencephalography during hemiplegic migraine attacks. Depressed activity contralateral to the hemiparesis was seen on electroencephalography during acute hemiplegic migraine attacks, which may be due to changes to calcium channels caused by the S218L mutation. Both parents were asymptomatic and did not carry the S218L mutation in their blood. This suggests the presence of mosaicism in the transmitting parent.

Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias

We compared atorvastatin with simvastatin-based therapies in a prospective observational study of 201 patients with severe hyperlipidaemia. Atorvastatin 10 mg therapy was substituted for simvastatin 20 mg, 20 mg for 40 mg, 40 mg for simvastatin 40 mg plus resin, and 80 mg for simvastatin-fibrate-resin therapy. Lipid and safety profiles were assessed. Atorvastatin reduced total cholesterol by 31 +/- 11-40 +/- 14% vs. 25 +/- 12-31 +/- 11%; LDL by 38 +/- 16-45 +/- 18% vs. 31 +/- 18-39 +/- 18% and geometric mean triglycerides by 29.3-37.3% vs. 16.6-24.8%, but reduced HDL 11% +/- 47% at 80 mg compared with a 16% +/- 34% increase with simvastatin-based therapy. Target LDL < 3.5 mmol/l was achieved more often with atorvastatin (63% vs. 50%; p < 0.001). Atorvastatin increased geometric mean fibrinogen by 12-20% vs. a 0-6% fall with simvastatin (p << 0.001). Side effects were noted in 10-36% of patients, including one case of rhabdomyolysis, and 36% discontinued therapy. These data suggest that atorvastatin is more effective than current simvastatin-based therapies in achieving treatment targets in patients with familial hypercholesterolaemia but at the expense of a possible increase in side-effects. This issue needs further study in randomized controlled trials.