Epidemiology of neurofibromatosis type 1 in Finland : incidence, mortality, pregnancies and congenital malformations

Neurofibromatosis type 1 (NF1) is a dominantly inherited cancer syndrome, which is caused by mutations in the NF1 gene. Because of the high mutation rate of the gene, approximately half of the patients have a new mutation, while none of the parents have the disorder. The incidence of NF1 is estimated to be approximately 1:3,000. The best-known symptoms of NF1 are neurofibromas on the skin, but NF1 is a multisystem disorder associated with a decreased overall survival and increased risk for pathologies such as cancer, learning difficulties, epilepsy and speech defects. While there are some previous epidemiological studies on NF1-associated pregnancies and mortality of NF1, data is very limited. No epidemiological data is reported on birth size or overall risk for congenital malformations in NF1. We have acquired a nationwide cohort of approximately 1,500 patients with a confirmed diagnosis for NF1, and ten matched controls per NF1 patient were collected. The data was linked with administrative registers to study incidence, mortality, pregnancies, birth size and congenital malformations of NF1. We observed that the incidence of NF1 in Finland was approximately 1:2,000, which is higher than previously generally accepted. Mortality of NF1 was considerably higher than in the general population. Pregnancy duration was shortened by a fetus with NF1, and the risk for several pregnancy and delivery complications was increased among NF1 mothers. Birth weight was decreased by having a mother with NF1, while having NF1 present in the child increased it. The risk for congenital malformations was almost three-fold among NF1 children compared to matched controls. Our study highlights a wide spectrum of ailments that NF1 causes, and the results can be utilized when guidelines of treatment and follow-up of NF1 are developed.Neurofibromatoosi 1 Suomessa: epidemiologinen tutkimus ilmaantuvuudesta, kuolleisuudesta, raskauksista ja epämuodostumista Neurofibromatoosi 1 (NF1) on vallitsevasti periytyvä monille syöpätyypeille altistava oireyhtymä, joka johtuu NF1-geenin mutaatioista. NF1-geenissä tapahtuu hyvin herkästi mutaatioita, minkä vuoksi noin puolella potilaista on uusi mutaatio ja vain puolella potilaista on vanhemmilta peritty sairaus. NF1:n ilmaantuvuuden on arvioitu olevan noin 1:3000. Parhaiten NF1:n oireista tunnetaan iholta löytyvät hyvänlaatuiset neurofibroomakasvaimet, mutta kyseessä on monen elimen oireyhtymä. NF1:n onkin havaittu lisäävän kuolleisuutta sekä riskiä sairastua mm. syöpään sekä epilepsiaan. Lisäksi esim. oppimisvaikeudet ovat yleisiä NF1-potilailla. Epidemiologinen tutkimustieto NF1:n vaikutuksista kuolleisuuteen, raskauksiin ja synnytyksiin on niukkaa, eikä epidemiologista tietoa ole lainkaan NF1:n vaikutuksesta lapsen syntymäkokoon tai yleiseen epämuodostumariskiin. Tutkimusta varten muodostettiin koko maan kattava noin 1500 varmistetun NF1-potilaan ryhmä, ja jokaiselle potilaalle kerättiin kymmenen kaltaistettua verrokkihenkilöä. Valtakunnallisten rekisteritietojen avulla tutkittiin NF1:n ilmaantuvuutta sekä oireyhtymän vaikutusta raskauksiin, syntymäkokoon sekä epämuodostumariskiin. Tutkimuksessa havaittiin, että NF1:n ilmaantuvuus Suomessa on n. 1:2000, eli NF1 on selvästi aikaisempaa arvioitua yleisempi. NF1-potilaiden kuolleisuus oli suurentunut merkitsevästi verrattuna muuhun väestöön. Lapsen NF1 lyhensi raskaudenkestoa ja raskauskomplikaatioiden riski oli suurentunut NF1-äideillä. Äidin NF1 pienensi lapsen syntymäpainoa, mutta lapsen NF1:n vaikutus painoon oli päinvastainen. NF1- lapsen epämuodostumariski oli lähes kolminkertainen kontrolliryhmään verrattuna. Tuloksemme osoittavat, että NF1:llä on laajoja ja osittain aikaisemmin tuntemattomia vaikutuksia raskauksiin ja synnytyksiin. Tutkimustuloksia voidaan käyttää hyväksi laadittaessa NF1:n seuranta- ja hoitosuosituksia

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

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.Peer reviewe

Tuberoosiskleroosi - suomalainen diagnoosi- ja seurantasuositus

•Tuberoosiskleroosia sairastavat potilaat tarvitsevat systemaattista, monen erikoisalan seurantaa läpi elämän. •Tavoitteena on haitallisten tai jopa hengenvaarallisten elinmuutosten varhainen toteaminen ja hoito. •Epilepsian tehokkaalla hoidolla ja kehityksen oikea-aikaisella tuella pyritään vaikuttamaan potilaiden kehitys¬ennusteeseen ja neuropsykiatristen häiriöiden esiintymiseen. •Tässä suosituksessa esitetään diagnosointi- ja seurantavaiheessa tarvittavat tutkimukset ja niiden toteutus, jossa hyödynnetään sekä erikoissairaanhoidon että perusterveydenhuollon palveluja.Peer reviewe

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.Peer reviewe

Haploinsufficiency of the NF1 gene is associated with protection against diabetes

BACKGROUND: The hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of the NF1 gene. Here, we used a cohort of 1410 patients with NF1 to study the association of the NF1 gene with type 1 (T1D) and type 2 diabetes (T2D). METHODS: A total of 1410 patients were confirmed to fulfil the National Institutes of Health diagnostic criteria for NF1 by individually reviewing their medical records. The patients with NF1 were compared with 14 017 controls matched for age, sex and area of residence as well as 1881 non-NF1 siblings of the patients with NF1. Register-based information on purchases of antidiabetic medication and hospital encounters related to diabetes were retrieved. The Cox proportional hazards model was used to calculate the relative risk for diabetes in NF1. RESULTS: Patients with NF1 showed a lower rate of T2D when compared with a 10-fold control cohort (HR 0.27, 95% CI 0.17 to 0.43) or with their siblings without NF1 (HR 0.28, 95% CI 0.16 to 0.47). The estimates remained practically unchanged after adjusting the analyses for history of obesity and dyslipidaemias. The rate of T1D in NF1 was decreased although statistically non-significantly (HR 0.58, 95% CI 0.27 to 1.25). CONCLUSION: Haploinsufficiency of the NF1 gene may protect against T2D and probably T1D. Since NF1 negatively regulates the Ras signalling pathway, the results suggest that the Ras pathway may be involved in the pathogenesis of diabetes.Peer reviewe