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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Orphanet Journal of Rare Diseases 1/2018

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

Orphanet Journal of Rare Diseases > Ausgabe 1/2018
Jussi Leppävirta, Roope A. Kallionpää, Elina Uusitalo, Tero Vahlberg, Minna Pöyhönen, Juha Peltonen, Sirkku Peltonen



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.


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.


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).


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.
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