P012 A delayed diagnosis of neurofibromatosis type 1 during pregnancy

Abstract Neurofibromatosis type 1 (NF1) is a multisystem autosomal dominant disorder with a prevalence of 1 in 3500 live births. It is caused by mutation of a tumour suppressor gene NF1, located in the long arm of chromosome 17 (17q11.2). There is a 1 : 1 ratio for spontaneous vs. inherited mutations. Mutations resulting in the loss of function of neurofibromin leave cells susceptible to uncontrolled proliferation via overstimulation of protein kinase pathways by unchecked Ras proteins. The common cutaneous manifestations of NF1 – café au lait macules, neurofibromas and intertriginous freckling, appear in most patients by the age of 20 years. Neurofibromas typically first appear during puberty, resulting in questions regarding the role of steroid hormones. To support the hypothesis that steroid hormones contribute to neurofibroma development, we present a new diagnosis of NF1 following the eruption of neurofibromas in a 32-year-old woman during her first trimester of pregnancy. A patient presented in the third trimester of her first pregnancy, with a long history of four unchanged cutaneous papules affecting the right breast. During the first trimester these had increased in number, size and extent of distribution. The patient had no previous history of skin abnormalities, scoliosis, malignancy or developmental delay. There was no family history of NF1. Examination revealed over 50 skin-coloured papules in a segmental distribution involving the entire right arm, right chest and right thigh, as well as five café au lait macules involving the trunk. Histological analysis confirmed neurofibromas, supporting the NF1 clinical diagnosis, which was positive on genetic testing. The pregnancy progressed uneventfully. The patient’s mother subsequently tested positive for NF1 mutation without having any symptoms or signs. In vitro studies have demonstrated that up to 86% of cutaneous neurofibromas possess progesterone receptors; they have also found high levels of heterogeneity when examining the proliferation of NF1 cell cultures in response to steroid hormones. It is unclear why levels of steroid hormones at birth or during puberty are enough to trigger formation of neurofibromas in some patients but not others. This represents an important area for research regarding whether further tumour factors, such as epigenetics, may alter the response to environmental and genetic triggers. Consideration of NF1 as a diagnosis in people of all ages is essential, particularly in view of the increased risks it presents during pregnancy. Patients with NF1 are more likely to develop gestational hypertension, pre-eclampsia and intrauterine growth restriction. Appropriate prenatal counselling and imaging for detection of spinal soft tissue tumours prior to epidural use are additional important aspects of patient management. These were not possible for our patient due to her late diagnosis.