Background: Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families. Patients and methods: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1. Results: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p = 0.002 and p Conclusion: This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer.

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Anticipation in familial pancreatic cancer

Objective: The main clinico-diagnostic features, risk factors and associated diseases of cavernous malformations (CMs), also called cavernous angiomas or cavernomas, of the central

Cavernous Malformations of the Central Nervous System in the Pediatric Age Group

Cerebral cavernous malformations (CCM) are vascular anomalies, sometimes inherited as an autosomal dominant trait, which can cause strokes and seizures. Recently, mutations of the CCM1 gene (chromosome 7q) have been found in a subset of families. The authors found 10 new mutations by screening 29 families and five seemingly sporadic cases of CCM. The mutations predicted truncation of the Krit1 mRNA encoded by CCM1, supporting the contention that CCM result from loss of Krit1 protein function and the possibility that this protein acts as a tumor suppressor.

CCM1 gene mutations in families segregating cerebral cavernous malformations.

Based on the latest gnomAD dataset, the prevalence of symptomatic hereditary cerebral cavernous malformations (CCMs) prone to cause epileptic seizures and stroke-like symptoms was re-evaluated in this review and calculated to be 1:5,400-1:6,200. Furthermore, state-of-the-art molecular genetic analyses of the known CCM loci are described which reach an almost 100% mutation detection rate for familial CCMs if whole genome sequencing is performed for seemingly mutation-negative families. An update on the spectrum of CCM1, CCM2, and CCM3 mutations demonstrates that deep-intronic mutations and submicroscopic copy-number neutral genomic rearrangements are rare. Finally, this review points to current guidelines on genetic counselling, neuroimaging, medical as well as neurosurgical treatment and highlights the formation of active patient organizations in various countries.

/pdf/cerebral-cavernous-malformations-an-update-on-prevalence-mug5d6mkvc.pdf

Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling.

The authors report the case of a 45-year-old woman with medically intractable trigeminal neuralgia (TN) in whom a good clinical response to partial sectioning of the trigeminal nerve was attained. No evidence of vascular compression was found intraoperatively. Several other members of her family, involving three generations, also suffered from TN. The treatment of all affected patients is discussed in the context of a literature review in which the controversies surrounding the origins of the disease and treatment options for patients with the familial variant of TN are addressed.

Familial trigeminal neuralgia. Case report and review of the literature.

OBJECTIVES: Anticipation has been linked to unstable trinucleotide repeats in many neurological disorders. We examined the hypothesis of genetic anticipation in familial cavernous angioma (FCA) of the central nervous system. MATERIAL AND METHODS: The mean ASO of affected individuals was compared between successive generations in 55 families. Intergenerational pair-wise comparisons were employed to avoid several ascertainment biases. Regarding severity of disease both type of manifestation and number of cavernous angiomas were compared between generations. RESULTS: The mean ASO decreased significantly both from the first to the second generation (31.6 vs 17.8 years; P = 0.000) and from the second to the third generation (17.8 vs 6.7 years; P = 0.002). The pair-wise comparisons also showed significantly earlier ASO. No clear evidence for anticipation with regard to severity of disease was found. CONCLUSIONS: Molecular genetic studies will determine whether trinucleotide repeats are the underlying mechanism for our observation of anticipation in FCA.

D. Könü

Papers

Anticipation in familial cavernous angioma: ascertainment bias or genetic cause