Publications by authors named "Marie Louise Mølgaard Binderup"

11 Publications

  • Page 1 of 1

von Hippel-Lindau disease: Diagnosis and factors influencing disease outcome.

Dan Med J 2018 Mar;65(3)

von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition caused by mutations in the VHL tumor suppressor gene. VHL mutation-carriers are at life-long risk of multi-organ tumor development. The mainstay of vHL management is close surveillance and surgical tumor removal. The disease has been reported to be fully penetrant at 60 years of age, and has a highly variable phenotype, which complicates vHL management and causes distress and uncertainty for affected families. vHL survival has historically been poorer than the survival of the general population, with a median life expectancy for vHL patients of only 49 years. vHL life expectancy is expected to be improved by better surveillance, tumor diagnosis, and treatment approaches, although this has not
yet been directly demonstrated. The prevalence of vHL is between 1 in 39,000 and 1 in 91,000 individuals, and the birth incidence is between 1 in 36,000 and 1 in 45,500 live births in different populations. Based on these estimates, vHL is underdiagnosed in Denmark, and many undiagnosed families are not offered genetic counseling or prophylactic surveillance.
We aimed to assess 1) how the rate of new manifestation development is influenced by age, sex, genotype, tumor location, and pregnancy, 2) how vHL survival has developed over time, and is affected by sex, genotype, and surveillance attendance, 3) to determine the prevalence and incidence of vHL, and 4) to calculate vHL penetrance based on an unselected national cohort. 
We included almost all diagnosed vHL patients in Denmark in a retrospective cohort study. We further used the national health registers to find individuals who had a missed vHL diagnosis despite fulfilling the clinical diagnostic criteria.
We found that the risk of new vHL manifestations varies with age, genotype, and tumor location. The risk of new retinal tumors is highest in the patients' teenage years, while cerebellar tumors developed at the highest rates in patients' thirties. Patients with truncating mutations had higher rates of new manifestation diagnosis than patients with missense mutations. Men tend to have higher manifestation rates in adulthood compared to women, and pregnancy was associated with a lower frequency of new manifestations. vHL survival has improved over time, and is getting closer to that of their siblings without vHL and the general population. Survival is significantly influenced by a patient's birth year, sex, and genotype. We estimate the mean life expectancy of VHL mutation-carriers born in 2000 to be 67 years for men and 60 years for women. We estimate the vHL prevalence to be about 1 in 46,900 individuals and the birth incidence to be about 1 in 27,300 live births. We found a penetrance at age 60 of 87%, and only 80% among pa-tients who have not attended surveillance prior to diagnosis, which is considerably lower than previous estimates. 
Our findings form the basis of a more targeted vHL surveillance and counseling. The lower age-related penetrance greatly influences risk assessment in a clinical genetic setting. Even though the prevalence has increased over recent years, vHL is still underdiagnosed, and there is a need for increased awareness about the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2018

Retinal hemangioblastoma: prevalence, incidence and frequency of underlying von Hippel-Lindau disease.

Br J Ophthalmol 2018 07 28;102(7):942-947. Epub 2017 Sep 28.

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Background And Aims: We aimed to determine the frequency of von Hippel-Lindau disease (vHL) as the underlying cause of retinal hemangioblastoma and to estimate retinal hemangioblastoma incidence and prevalence in a national cohort study.

Methods: Through the national patient register and vHL research database, we identified 81 patients diagnosed with a retinal hemangioblastoma in Denmark between 1977 and 2014. Consent was obtained for 54 living and 10 deceased patients with retinal hemangioblastoma. For each participant, we collected medical records and family information. Almost all (63 of 64) participants were or had previously been tested for mutations in the gene.

Results: Overall, 84% of the participants (54 of the 64) had vHL. Compared with the non-vHL patients, the vHL patients had their first retinal hemangioblastoma at a younger age (22.5 vs 40 years), and were more likely to have an asymptomatic first hemangioblastoma (80% vs 20%). Overall, 76% (41 of 54) of the vHL patients had a family history of vHL, while none of the patients without vHL did. Despite the rarity of the disease, on average more than eight new tumours are diagnosed each year due to multiple tumour development in vHL patients. The estimated prevalence of patients with retinal hemangioblastoma was up to 1 in 73 080 individuals.

Conclusion: In the first national study in which almost all participants were genetically tested, vHL was the underlying cause of retinal hemangioblastoma in 84% of cases; more often than previously reported. We recommend that genetic and clinical vHL screening should be performed in all patients with retinal hemangioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjophthalmol-2017-310884DOI Listing
July 2018

Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the Mutation p.P81S (c.241C>T).

Curr Genomics 2017 Feb;18(1):93-103

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Background: Evaluation of the pathogenicity of a gene variant of unknown significance (VUS) is crucial for molecular diagnosis and genetic counseling, but can be challenging. This is especially so in phenotypically variable diseases, such as von Hippel-Lindau disease (vHL). vHL is caused by germline mutations in the VHL gene, which predispose to the development of multiple tumors such as central nervous system hemangioblastomas and renal cell carcinoma (RCC).

Objective: We propose a method for the evaluation of VUS pathogenicity through our experience with the VHL missense mutation c.241C>T (p.P81S).

Method: 1) Clinical evaluation of known variant carriers: We evaluated a family of five VHL p.P81S carriers, as well as the clinical characteristics of all the p.P81S carriers reported in the literature; 2) Evaluation of tumor tissue via genetic analysis, histology, and immunohistochemistry (IHC); 3) Assessment of the variant's impact on protein structure and function, using multiple databases, in silico algorithms, and reports of functional studies.

Results: Only one family member had clinical signs of vHL with early-onset RCC. IHC analysis showed no VHL protein expressed in the tumor, consistent with biallelic VHL inactivation. The majority of in silico algorithms reported p.P81S as possibly pathogenic in relation to vHL or RCC, but there were discrepancies. Functional studies suggest that p.P81S impairs the VHL protein's function.

Conclusion: The VHL p.P81S mutation is most likely a low-penetrant pathogenic variant predisposing to RCC development. We suggest the above-mentioned method for VUS evaluation with use of different methods, especially a variety of in silico methods and tumor tissue analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389202917666160805153221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321774PMC
February 2017

Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark.

Eur J Hum Genet 2017 02 14;25(3):301-307. Epub 2016 Dec 14.

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Von Hippel-Lindau disease (vHL) is a rare hereditary tumour predisposition with multiorgan involvement that is not always easily recognized. The disease is reported to be almost fully penetrant at age 60 years. Previous estimates of vHL prevalence and incidence are all regional and vary widely. Most are >20 years old and prone to selection bias because of inclusion of only clinically affected vHL patients who were diagnosed before genetic testing was available. In an unselected cohort of all known Danish carriers of a disease-causing VHL variant, we assessed vHL penetrance on a national basis. We further used national health registers to identify individuals who fulfilled the clinical diagnostic vHL criteria based on their registered diagnostic codes, but had not been diagnosed with vHL. We also assessed the medical histories of first-degree relatives to identify familial cases. This study gives the first national estimates of vHL prevalence (1 in 46 900 individuals) and birth incidence (1 in 27 300 live births). vHL has been underdiagnosed in Denmark, and as many as 25% of the overall vHL cohort (diagnosed+undiagnosed patients) have a missed diagnosis in spite of fulfilling the international diagnostic criteria. We found an overall penetrance of 87% at age 60 years. When considering only vHL patients who have not attended surveillance, 20% will still be asymptomatic at age 60 years. This should be considered in the context of genetic counselling, especially when assessing the risk of vHL in asymptomatic adult first-degree relatives who are often not genetically tested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2016.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315510PMC
February 2017

Survival and causes of death in patients with von Hippel-Lindau disease.

J Med Genet 2017 01 18;54(1):11-18. Epub 2016 Aug 18.

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Background: Historically, the survival of patients with von Hippel-Lindau disease (vHL) has been poorer than that of the general population. We aimed to determine whether the survival of VHL mutation carriers and their risk of vHL-related death has changed over time and how it has been affected by sex, genotype and surveillance attendance.

Methods: In a retrospective cohort study, we included all known Danish vHL families with a VHL mutation. We assessed the survival and causes of death for 143 VHL mutation carriers using Cox regression models and compared vHL survival with that of 137 siblings without vHL. vHL life expectancy was compared with the general population using a relative survival model.

Results: The estimated mean life expectancies for male and female patients born in 2000 were 67 and 60 years, respectively. Survival is influenced by the sex and genotype of the patient. Female patients have a significantly higher risk of vHL-related death than male patients (HR=2.25, 95% CI 1.20 to 4.20, p=0.011). Overall, 79% (53 of 67) of deaths were vHL-related, but the risk of vHL-related death has decreased over time, as has the frequency of renal cell carcinoma (RCC)-related death. Surveillance is especially beneficial for truncating mutation carriers, who have the greatest RCC and central nervous system (CNS) hemangioblastoma risk.

Conclusions: vHL survival has improved over time and has become closer to that of siblings without vHL and the general population. Even though the risk of vHL-related death has decreased significantly, the main cause of death is still CNS hemangioblastomas and hence improved treatment options are essential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2016-104058DOI Listing
January 2017

New von Hippel-Lindau manifestations develop at the same or decreased rates in pregnancy.

Neurology 2015 Oct 25;85(17):1500-3. Epub 2015 Sep 25.

From the Departments of Cellular and Molecular Medicine (M.L.M.B., E.B.-J., M.L.B.) and Biostatistics (E.B.-J.), University of Copenhagen, Denmark.

Objective: In a national retrospective cohort study, we aimed to determine the effect of pregnancy on new von Hippel-Lindau (vHL) tumor development during pregnancy and at 1, 3, and 5 years after conception.

Methods: We included 52 VHL mutation carriers (26 men and 26 women) with 581 manifestations diagnosed throughout their lifetimes. We analyzed age-dependent manifestation rates using Poisson regression. We compared the women's rates in intervals where they had been pregnant with their age-matched nonpregnant intervals. We investigated possible long-term effects using pregnancy intervals of increasing lengths of 1, 3, and 5 years after conception. Furthermore, we compared age-related manifestation rates for women and men.

Results: From birth to the participants' current age, 581 manifestations were diagnosed; mean age was 37.5 years (range 2-64 years). Seventeen women had completed 30 pregnancies. Manifestation rates in women's pregnant intervals were lower compared with their age-matched nonpregnant intervals (1 year: hazard ratio [HR] = 0.439, 95% confidence interval [CI] 0.131-1.474, p = 0.18; 3 years: HR = 0.412, 95% CI 0.214-0.796, p = 0.0083; and 5 years: HR = 0.450, 95% CI 0.136-1.489, p = 0.19). Men and women had similar manifestation rates, both increasing from their 20s.

Conclusions: Pregnancy does not aggravate vHL tumor development, and we neither discourage pregnancy in VHL mutation carriers nor recommend intensified surveillance during pregnancy. The pregnancy effect is not due to concurrence of a naturally milder tumor development in women's fertile ages, as the rate of new tumor development increases for both men and women from 20 years of age, even more in men than in women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000002064DOI Listing
October 2015

Risk of new tumors in von Hippel-Lindau patients depends on age and genotype.

Genet Med 2016 Jan 2;18(1):89-97. Epub 2015 Apr 2.

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Purpose: The von Hippel-Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype.

Methods: In a national cohort study, we included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person-years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Manifestation rates were analyzed using Poisson regression and compared in groups of different ages, tumor sites, and genotypes.

Results: The rate of new tumor development varied significantly with age and was highest at 30-34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval: 1.06-3.24, P value = 0.031).

Conclusion: The rate of new manifestation development is not constant throughout the life span of vHL patients; instead, it varies significantly with age and genotype and depends on anatomical location. Retinal surveillance is crucial during the teenage years, whereas cerebellar surveillance is especially important in adulthood.Genet Med 18 1, 89-97.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2015.44DOI Listing
January 2016

The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24.

Fam Cancer 2015 Sep;14(3):393-400

Department of Cellular and Molecular Medicine, Faculty of Health, Panum Institute 24.4, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark.

Hereditary colorectal cancer accounts for approximately 30% of all colorectal cancers, but currently only 5% of these families can be explained by highly penetrant, inherited mutations. In the remaining 25% it is not possible to perform a gene test to identify the family members who would benefit from prophylactic screening. Consequently, all family members are asked to follow a screening program. The purpose of this study was to localize a new gene which causes colorectal cancer. We performed a linkage analysis using data from a SNP6.0 chip in one large family with 12 affected family members. We extended the linkage analysis with microsatellites (STS) and single nucleotide polymorphisms (SNP's) and looked for the loss of heterozygosity in tumour tissue. Furthermore, we performed the exome sequencing of one family member and we sequenced candidate genes by use of direct sequencing. Major rearrangements were excluded after karyotyping. The linkage analysis with SNP6 data revealed three candidate areas, on chromosome 2, 6 and 11 respectively, with a LOD score close to two and no negative LOD scores. After extended linkage analysis, the area on chromosome 6 was excluded, leaving areas on chromosome 2 and chromosome 11 with the highest possible LOD scores of 2.6. Two other studies have identified 11q24 as a candidate area for colorectal cancer susceptibility and this area is supported by our results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-015-9791-2DOI Listing
September 2015

Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition.

Dan Med J 2013 Dec;60(12):B4763

Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgardsvej 21 C, 8200 Aarhus N, Denmark.

These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations in the VHL gene. vHL is inherited in an autosomal dominant manner. Predisposed individuals are advised to undergo prophylactic examinations, as they are at lifelong risk of developing multiple cysts and tumours, especially in the cerebellum, the spinal cord, the retina (hemangioblastomas), the kidneys (renal cell carcinoma), the adrenal glands (pheochromocytoma), the pancreas, as well as in other organs. As many different organs can be affected, several medical specialities often take part in both diagnosis and treatment of manifestations. vHL should be suspected in individuals with a family history of the disease, and/or in individuals with a vHL-associated manifestation; i.e. a hemangioblastoma in the retina or the central nervous system, familial or bilateral pheochromocytomas, familial, multiple, or early onset renal cell carcinomas, and in individuals with an endolymphatic sac tumour in the inner ear. Individuals suspected of vHL should be referred to a department of clinical genetics for genetic work-up and counselling as well as have a clinical work-up to identify any undiagnosed vHL-associated manifestations. This guideline describes the elements of the clinical diagnostic work-up, as well as the genetic work-up, counselling, and mutation screening. Individuals who are affected with vHL, individuals at risk of vHL, and VHL-mutation carriers are advised to follow the surveillance program which consists of regular prophylactic examinations relevant to different age groups. The examinations are recommended to start in infancy with annual paediatric examinations and ophthalmoscopy until the age of five years. From five to 14 years, annual plasma-metanephrine and plasma-normetanephrine tests, as well as annual hearing examinations are added. Also, an MRI (Magnetic Resonance Imaging) examination of the CNS and abdomen should be done between the ages of eight and 14 years. After the age of 15 years, individuals should be referred to: a) annual ophthalmoscopy in dilation, b) annual neurological examination, c) every two years: MRIs of the CNS, including the inner ear, d) annual ultrasound/MRI of the abdomen, e) annual plasma-metanephrine, plasma-normetanephrine, and plasma-chromogranin A tests, and f) annual hearing examination at a department of audiology. It is advised that one doctor takes on the responsibility of coordination of and referral to the many examinations, and the communication with the patient. To facilitate the coordination, and especially for the patients' own use, a mobile chart can be used. In 2012, the Danish vHL Coordination Group established a national vHL database comprising individuals with vHL and their relatives, as well as individuals examined for vHL. The database is designated to be a treatment and diagnostic instrument, as well as a tool in future vHL research in Denmark.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2013

von Hippel-Lindau disease: deafness due to a non-MRI-visible endolymphatic sac tumor despite targeted screening.

Int J Audiol 2013 Nov 5;52(11):771-5. Epub 2013 Sep 5.

* Department of Cellular and Molecular Medicine, University of Copenhagen , Copenhagen , Denmark.

Objective: Endolymphatic sac tumours (ELSTs) of the inner ear occur in 16% of patients with the hereditary tumor syndrome von Hippel-Lindau disease (vHL). ELSTs of all sizes can cause irreversible hearing loss which can, however, be prevented through early diagnosis and treatment. We aim to emphasize the challenges of prophylactic ELST screening and to explore the role of audiometry in pre-symptomatic ELST screening.

Design: For a period of 17 years our patient was screened for ELSTs with inner-ear MRI (magnetic resonance imaging), audiometry, and clinical interviews.

Study Sample: A male vHL patient who became deaf in one ear due to a radiologically undetectable ELST.

Results: Despite annual MRIs, the ELST was not visible until four months after onset of deafness when it appeared as a 1.4 × 1.4 mm tumor mass. Although his hearing was objectively within normal limits for the first 14 years, a distinct pattern of low-frequency hearing loss could retrospectively be seen at all audiometries.

Conclusions: Audiometry is a candidate screening tool for detection of non-symptomatic pre-MRI-visible ELSTs, and we have initiated an international collaborative study to further determine its application. At present, we suggest an ELST screening protocol of yearly audiological assessment and inner ear MRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/14992027.2013.824117DOI Listing
November 2013

[Research training is inadequate among future medical doctors].

Ugeskr Laeger 2012 Oct;174(43):2624-7

PUFF, c/o Studenterhuset Panum, Nørre Allé 8, Copenhagen.

This questionnaire survey investigated interest and activity in pregraduate research among 643 medical students at the Faculty of Health and Medical Sciences at the University of Copenhagen. We find, that although the students show great interest and motivation for research, very few have actual research experience. The students described suboptimal research training, lack of tutoring and facilitation as well as of career counselling. Also, conditions for pregraduate research activities are unequal among the faculties of health sciences in Denmark.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2012
-->