Increased risk for dementia in neurofibromatosis type 1.

PURPOSE: To determine the risk for dementia in neurofibromatosis type 1 (NF1) using a Finnish nationwide cohort of individuals with NF1, and data from national registries. METHODS: A Finnish cohort of 1,349 individuals with confirmed NF1 according to the US National Institutes of Health (NIH) diagnostic criteria was compared with a control cohort of 13,870 individuals matched for age, sex, and area of residence. Dementia-related hospital visits were retrieved from the Finnish Care Register for Health Care using International Classification of Diseases, 10th revision (ICD-10) diagnosis codes G30 and F00-F03. Purchases of antidementia drugs were queried with Anatomical Therapeutic Chemical (ATC) classification code N06D from the drug reimbursement register maintained by the Social Insurance Institution of Finland. The follow-up spanned 1998-2014. RESULTS: Totals of 16 and 165 individuals with at least two dementia-related diagnoses or drug purchases were identified in the NF1 and control cohorts, respectively. The hazard ratio for dementia in NF1 was 1.67 (95% confidence interval [CI] 1.00-2.80, P = 0.050). In an analysis stratified by the type of dementia, the risk for Alzheimer disease was increased in NF1 compared to controls with a hazard ratio of 2.88 (95% CI 1.47-5.66, P = 0.002). CONCLUSION: Dementia and especially Alzheimer disease are previously unrecognized neurological complications of NF1.

Neurofibromatosis type 1 of the child increases birth weight.

Neurofibromatosis type 1 (NF1) is associated with reduced adult height, but there are no cohort studies on birth size. This retrospective study includes a cohort of 1,410 persons with NF1 and a matched comparison cohort from the general population. Figures for birth size were retrieved from the administrative registers of Finland, and the data were converted to standard deviation scores (SDS), defined as standard deviation difference to the reference population. The birth weight among infants with NF1 was higher than among infants without the disorder (adjusted mean difference [95% confidence interval]: 0.53 SDS [0.19-0.87]), as was the head circumference at birth (0.58 SDS [0.26-0.90]). The birth length of the NF1 infants did not differ significantly from the comparison cohort. The birth weight in the group consisting of NF1 and non-NF1 infants of NF1 mothers was lower than among infants of mothers in the comparison cohort (-0.28 SDS [-0.51 to -0.06]), as was the birth length (-0.22 SDS [-0.45 to 0.00]). In conclusion, the birth weight and head circumference of persons with NF1 are significantly higher than those of persons without the disorder. NF1 of the mother reduces birth weight and birth length of the infant.

Pediatric malignancies in neurofibromatosis type 1: A population-based cohort study.

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome with an incidence of 1:2,000. Patients with NF1 have an increased cancer risk and mortality, but there are no population-based cohort studies specifically investigating the risk of childhood malignancies. We used the Finnish NF1 cohort to analyze the incidence, risk and prognosis of malignancies in NF1 patients <20 years of age. Persons born in 1987-2011 were included, and 524 persons were followed through the files of the Finnish Cancer Registry from birth up to age 20 years. This amounted to 8,376 person years. Fifty-three patients had cancer <20 years of age, yielding a standardized incidence ratio (SIR) of 35.6. The most frequent location of pediatric cancers was the central nervous system (CNS); there were 45 cases and the SIR was 115.7. Exclusion of 22 optic pathway gliomas (OPGs) gave an SIR of 59.1 for the CNS and 21.6 for all cancers. There were nine malignant peripheral nerve sheath tumors (MPNSTs); their cumulative risk was 2.7% by age 20. No cases of leukemia were observed. NF1 patients showed considerable excess mortality with a standardized mortality ratio (SMR) of 73.1. The survival of NF1 patients with CNS tumors other than OPGs did not differ from that of non-NF1 controls (HR 0.64, 95% CI 0.23 to 1.76). In conclusion, brain tumors in childhood and MPNSTs in adolescence are malignancies of major concern in patients with NF1. The risk for myeloid malignancies may not be as high as suggested in the literature.

Congenital anomalies in neurofibromatosis 1: a retrospective register-based total population study.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a dominantly inherited Rasopathy caused by mutations in the NF1 gene on chromosome 17. NF1 has been connected to congenital anomalies, e.g., in the skeletal and cardiovascular systems, but the overall incidence of anomalies is unknown. In this retrospective register-based total population study conducted in Finland, the congenital anomalies in NF1 were evaluated. METHODS: One thousand four hundred ten patients with NF1 were identified by searching the medical records related to inpatient and outpatient hospital visits of patients with an associated diagnosis for NF1 in 1987-2011. Each diagnosis was confirmed by a thorough review of the medical records. Ten non-NF1 control persons per NF1 patient were collected from the Population Register Centre. NF1 patients and controls were linked to the Medical Birth Register and the Register of Congenital Malformations. Odds ratios (OR) and 95% confidence intervals (95% CI) for major congenital anomalies (MCA) were calculated. RESULTS: The OR for at least one MCA among NF1 children was almost threefold (adjusted OR 2.78, 95% CI 1.71-4.54) compared to controls matched for age, sex and municipality. NF1 children had a significantly increased risk of congenital anomalies in the circulatory (adjusted OR 3.35, 95% CI 1.64-6.83), urinary (adjusted OR 4.26, 95% CI 1.36-13.35) and musculoskeletal (adjusted OR 2.77, 95% CI 1.09-7.02) systems. Also, anomalies of the eye, ear, head and neck were more common among NF1 children than controls (adjusted OR 4.66, 95% CI 1.42-15.31). Non-NF1 children of mothers with NF1 did not have more anomalies than controls (adjusted OR 0.53, 95% CI 0.13-2.21). CONCLUSIONS: Children with NF1 have more MCAs than controls and close follow-up during pregnancy and the neonatal period is required if the mother or father has NF1. Non-NF1 children of mothers with NF1 do not have an increased risk for anomalies.

Prevalence of neurofibromatosis type 1 in the Finnish population.

PURPOSE: The incidence of neurofibromatosis 1 (NF1) is ~1/2,000 live births, but the current estimates of prevalence vary greatly. This retrospective total-population study was aimed at determining the prevalence of NF1 in Finland. METHODS: All secondary and tertiary referral centers of Finland were searched for NF1 patients. Patient records were manually reviewed and patients fulfilling the National Institutes of Health diagnostic criteria for NF1 were included. Prevalence on 31 December 2005 was determined. Data on incidence and survival were combined to refine the prevalence estimation. RESULTS: A total of 1,279 patients with NF1 were alive on 31 December 2005, yielding a prevalence of 1/4,088 (95% confidence interval (CI) 1/4,320-1/3,869). The survival of patients with NF1 was inferior compared with the general population (hazard ratio 3.10, 95% CI 2.73-3.53, P < 0.001). When the survival rates of NF1 patients and the Finnish population were combined with an estimate of NF1 incidence, a prevalence of 1/2,052 (95% CI 1/2,176-1/1,941) was estimated for NF1 in a population aged 0-74 years. CONCLUSION: NF1 is a much more common disorder than previously thought. A large proportion of NF1 patients may not be correctly identified by health-care systems or they do not seek secondary health care for their NF1.

The pregnancy in neurofibromatosis 1: A retrospective register-based total population study.

The objective of this retrospective total population study was to form a view of the pregnancies of the patients with neurofibromatosis type 1 (NF1). A cohort of 1,410 Finnish patients with NF1 was acquired by searching NF1-related inpatient and outpatient hospital visits and confirming the diagnoses by reviewing the medical records. Ten matched control persons per patient with NF1 were collected from Population Register Centre. Study persons were linked to data from Medical Birth Register and Care Register for Health Care through the personal identity code. Cesarean deliveries, hypertension/preeclampsia, and placental abruptions were more common among mothers with NF1 with adjusted odds ratios of 2.24 (95%CI 1.63-3.07), 1.96 (95%CI 1.18-3.24), and 13.40 (95%CI 4.26-42.13), respectively. The adjusted mean pregnancy duration was 0.65 (95%CI 0.42-0.88) weeks shorter among the mothers with NF1 than in the control group consisting of non-NF1 mothers giving birth to a non-NF1 child. The pregnancies of non-NF1 mothers giving birth to a NF1 child were 0.43 (95%CI 0.24-0.62) weeks shorter than in the control group. In summary, NF1 of the mother was associated with a shortened pregnancy and increased pregnancy complications. Also, the NF1 of the fetus slightly shortened pregnancy. Since mothers with NF1 are at increased risk for pregnancy complications, careful evaluation of their pregnancies is warranted.

Association of Catechol-O-methyltransferase polymorphism Val158Met and mammographic density: A meta-analysis.

OBJECTIVES: The Val158Met polymorphism in catechol-O-methyltransferase (COMT) enzyme reduces the methylation of catechol estrogens, which may affect mammographic density. High mammographic density is a known risk factor of breast cancer. Our aim was to perform meta-analysis of the effect of COMT Val158Met polymorphism on mammographic density. METHODS: Original studies reporting data on mammographic density, stratified by the presence of COMT Val158Met polymorphism, were identified and combined using genetic models Met/Val vs. Val/Val, Met/Met vs. Val/Val, Val/Met+Met/Met vs. Val/Val (dominant model) and Met/Met vs. Val/Met+Val/Val (recessive model). Subgroup analyses by breast cancer status, menopausal status and use of hormone replacement therapy (HRT) were also performed. RESULTS: Eight studies were included in the meta-analysis. The overall effect in percent mammographic density was -1.41 (CI -2.86 to 0.05; P=0.06) in the recessive model. Exclusion of breast cancer patients increased the effect size to -1.93 (CI -3.49 to -0.37; P=0.02). The results suggested opposite effect of COMT Val158Met for postmenopausal users of HRT versus premenopausal women or postmenopausal non-users of HRT. CONCLUSIONS: COMT Val158Met polymorphism may be associated with mammographic density at least in healthy women. Menopausal status and HRT should be taken into account in future studies to avoid masking of the underlying effects.

Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors.

BACKGROUND: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers. METHODS: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls. RESULTS: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P=0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population. CONCLUSIONS: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.

Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1.

PURPOSE: The current study was designed to determine the risk of cancer in patients with neurofibromatosis type 1 (NF1) by cancer type, age, and sex with unprecedented accuracy to be achieved by combining two total population-based registers. PATIENTS AND METHODS: A population-based series of patients with NF1 (N = 1,404; 19,076 person-years) was linked to incident cancers recorded in the Finnish Cancer Registry and deaths recorded in the national Population Register Centre between 1987 and 2012. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated for selected cancer types. Survival of the patients with cancer with and without NF1 was compared. RESULTS: In malignant peripheral nerve sheath tumors and CNS tumors, the cancers traditionally associated with NF1, we observed SIRs of 2,056 (95% CI, 1,561 to 2,658), and 37.5 (95% CI, 30.2 to 46.0), respectively, and SMRs of 2,301 (95% CI, 1,652 to 3,122) and 30.2 (95% CI, 19.1 to 45.2), respectively. We found an unequivocally increased risk for breast cancer. In particular, SIR was 11.1 (95% CI, 5.56 to 19.5) for breast cancer in women with NF1 age < 40 years; the overall SMR for breast cancer was 5.20 (95% CI, 2.38 to 9.88). Particularly high overall SIRs were observed in patients with NF1 age < 15 years: women, 87.6 (95% CI, 58.6 to 125); men, 45.6 (95% CI, 28.4 to 68.5). An estimated lifetime cancer risk for patients with NF1 was 59.6%. The 5-year survival of patients with cancer and NF1, excluding nervous tissue cancers, was worse than that of comparable patients with cancers without NF1 (54.0% v 67.5%; P = .01). CONCLUSION: Our results emphasize the general cancer proclivity of patients with NF1. These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1.

Neurofibromatosis type 1 gene mutation analysis using sequence capture and high-throughput sequencing.

Neurofibromatosis type 1 syndrome (NF1) is caused by mutations in the NF1 gene. Availability of new sequencing technology prompted us to search for an alternative method for NF1 mutation analysis. Genomic DNA was isolated from saliva avoiding invasive sampling. The NF1 exons with an additional 50bp of flanking intronic sequences were captured and enriched using the SeqCap EZ Choice Library protocol. The captured DNA was sequenced with the Roche/454 GS Junior system. The mean coverages of the targeted regions were 41x and 74x in 2 separate sets of samples. An NF1 mutation was discovered in 10 out of 16 separate patient samples. Our study provides proof of principle that the sequence capture methodology combined with high-throughput sequencing is applicable to NF1 mutation analysis. Deep intronic mutations may however remain undetectable, and change at the DNA level may not predict the outcome at the mRNA or protein levels.