Neurofibromatosis type 1 and pregnancy: Maternal complications and attitudes about prenatal diagnosis

Neurofibromatosis type 1 (NF1) is one of the most commoninherited genetic disorders with an incidence of 1/2,500 to 1/3,300 live births. The disease is caused by a mutation in NF1,atumorsuppressorgeneon17q11.2codingforneurofibromin,orbyamicrodeletioninvolvingtheNF1anditssurroundingregion.NF1is an autosomal dominant condition with complete penetranceafter childhood. Almost half the cases result from a de novomutation,whiletheothersinheritthealteredgenefromanaffectedparent.Thediseaseismarkedbypoorgenotype–phenotypecorre-lation and high inter- and intra-familial variability. Thereforegenetic counseling for affected individuals is hampered by thedifficulty in forecasting the clinical outcome for future offspring.Prenatal testing can be carried out if the parental mutation isknown, or if there are multiple affected family members, andlinkagehasbeenestablishedwithinthefamily;suchtestingisusefulfor establishing the presence of the parental mutation in the fetalDNA, but, as noted, cannot make any prediction about diseaseseverity [Origone et al., 2000; Terzi et al., 2009].Pregnancyhasalwaysbeenconsideredacriticaltimeforwomenwith NF1 because of reports of increased complications duringgestationarisingfrompre-eclampsia,pretermlabor,IUGR,hyper-tension, oligohydramnios, and spontaneous abortion and/or still-birth [Blickstein and Lancet, 1987; Sharma et al.,1991;Segalet al.,1999].Furthermore,casereportsdescribedtheassociationbetweenpregnancy and HELLP syndrome [Hagymasy et al., 1998; Agarwaletal.,2003],diagnosisofmalignantperipheralnervesheathtumor(MPNST)[Posmaaetal.,2003;KelloggandWatson,2010;Nelsonet al., 2010] and the occurrence of pheochromocytoma [Liu et al.,1996]. Although Dugoff and Sujansky [1996] presented a largestudy of pregnancy in 105 women, including data from 247gestations and noted a greater cesarean rate than in thegeneral population, they did not find an increased incidence ofany of these complications. However they did describe thegrowth of new neurofibromas and the enlargement ofexistingneurofibromasinmorethanthehalf.Althoughthemajor-ity of NF1 pregnant women did not report complications, someinvestigators proposed special monitoring in specific situations[Chetty et al., 2011].Here we describe our experience in the management of preg-nancies in women with NF1, and their attitude towards prenataldiagnosis. We included 43 women with a total of 79 pregnancies.Eightofthewomen(18.6%)werereferredforcareduringtheentiregestationalperiod,whiletheother35womenhadtheirpregnanciesdetected before joining our program; for them we obtained datafrom a review of their medical records and through personalinterviews. Among these 79 pregnancies, 65 were carried to termwhile the other 14 resulted in five first trimester spontaneousabortions, seven elective terminations (not related to concernsaboutNF1),andtwotherapeuticabortionsafterprenataldiagnosisthrough chorionic villus sampling (CVS). Two of the 65 full termpregnancies were twins, for a total of 67 live births.Forwomenvisitingourcenterbeforeandduringtheirpregnan-cies, we set up a model based on a set of preconceptional multi-specializedevaluationsthatwefeltwereaprerequisiteforaproperpersonalized management of pregnancy in women with NF1. The