Abstract
Neurofibromatosis type I (NF1) is an autosomal dominant condition that typically presents with cutaneous features, including neurofibromas and Lisch nodules. At the time of writing, vasculopathies are not part of the updated diagnostic criteria. We present the case of a 36-year-old woman with sudden-onset chest pain caused by a large haemothorax. It was discovered that this was likely secondary to a pseudoaneurysm in the seventh intercostal artery alongside mid-aortic syndrome with an aortic diameter of 3 mm. This patient had not previously been diagnosed and subsequently suffered a life-threatening complication. This case highlights delayed recognition and diagnosis of NF1 which ultimately resulted in life-threatening sequelae. We suggest noting higher index of suspicion of NF1 following identification of vasculopathy, and to consider earlier testing in atypical presentations.
Introduction
Neurofibromatosis type I (NF1), also known as von Recklinghausen Disease, is an autosomal dominant condition characterized by cutaneous features such as neurofibromas, café-au-lait macules and freckles in the groin or axilla [1–3]. This can often be accompanied by Lisch nodules located on the iris, optic gliomas and skeletal abnormalities [1]. Vasculopathy occurs in 8%–18% of paediatric patients with NF1, predominantly affecting the cerebral circulation, whilst the prevalence of large-vessel disease remains poorly defined [4]. Other case reports have noted renal artery stenosis [5], vertebral aneurysms [6], and dissection [7]. Revised diagnostic criteria [2] include cutaneous, ophthalmological and skeletal features. A diagnosis of NF1 requires ≥2 of the following: café-au-lait macules, freckling, neurofibromas, optic glioma, Lisch nodules, osseous lesion, heterozygous pathogenic NF1 variant. However, there is no mention of other larger vessel vasculopathies. This article describes and outlines a patient with NF1 who had met diagnostic criteria but presented to the healthcare services with life-threatening complications.
Case report
A 36-year-old woman presented to the emergency department following a witnessed collapse preceded by sudden-onset left-sided pleuritic chest pain. There were no cardiac symptoms or recent travel history. Past medical history included two miscarriages, hypertension, and childhood café-au-lait macules. Family history included a paternal cousin with NF1, although no the patient had not received a formal diagnosis.
Initial chest X-ray (seen in Fig. 1) demonstrated a large left pleural effusion. A computed tomography (CT) pulmonary angiogram excluded pulmonary embolism and revealed a large left haemothorax without an identifiable bleeding source. Additional findings included severe upper thoracic scoliosis, segmental dural ectasia, and left-sided expansion of the intervertebral foramen suggestive of meningoceles. These findings were consistent with a diagnosis of NF1.
Initial chest X-ray performed in the emergency department demonstrating large left-sided pleural effusion. Image courtesy of the Department of Medical Imaging, Royal Infirmary of Edinburgh, NHS Lothian.
A contrast-enhanced CT of the chest identified a suspected pseudoaneurysm of the left seventh posterior intercostal artery, considered the likely source of bleeding despite no active contrast extravasation. Imaging demonstrated aortic hypoplasia below the hiatus, with diameter of 3 mm (Figs 2 and 3) between the superior mesenteric artery and renal artery origins, which was considered to be longstanding.
CT chest with contrast axial view at the level of T12 vertebral body. Image courtesy of the Department of Medical Imaging, Royal Infirmary of Edinburgh, NHS Lothian.
CT aorta thoracic with contrast scan. Image courtesy of the Department of Medical Imaging, Royal Infirmary of Edinburgh, NHS Lothian.
The patient underwent successful endovascular coil embolization of the seventh intercostal artery pseudoaneurysm, followed by surgical evacuation of the haemothorax and chest drain insertion. No active bleeding point was identified intraoperatively, although a posterior meningocele was noted.
Following recovery, a multidisciplinary review concluded that imaging was consistent with mid-aortic syndrome involving the visceral and infra-renal aorta, with a small intimal flap at the right renal artery. Multi-branch revascularization was recommended.
Clinical genetic assessment identified multiple café au lait patches, neurofibromas and axillary freckling, fulfilling the clinical diagnostic criteria for NF1. Although genetic testing was not required to establish the diagnosis, it was performed for the purposes of future reproductive planning, including consideration of preimplantation genetic testing.
Discussion
This case highlights a rare but important complication of NF1. Although the patient fulfilled current diagnostic criteria, she was only referred after a life-threatening presentation. It also emphasises that vasculopathy is a recognized manifestation of NF1 despite its exclusion from current diagnostic criteria. Earlier recognition may result in fewer complications and improved patient safety.
The NF1 gene encodes neurofibromin, a tumour suppressor that negatively regulates Ras signalling [1, 8]. Although this mechanism explains many characteristic manifestations of NF1, the pathogenesis of NF1-associated vasculopathy remains incompletely understood. Proposed mechanisms include endothelial dysfunction, abnormal vascular smooth muscle proliferation, impaired vascular repair and neointimal hyperplasia resulting from dysregulated Ras signalling [8, 9]. Despite uncertainty regarding the precise mechanism, the association between NF1 and vasculopathy is well established [4, 5, 8, 10].
This patient had documented café-au-lait macules from 1999, but no other recorded features of NF1. Although café-au-lait macules alone were insufficient for diagnosis in 1999, it is unknown whether additional diagnostic features developed before her presentation. Notes from the patient’s general practitioner were unavailable, making it impossible to determine whether additional clinical features had been recognized before hospital admission. Similarly, interval imaging was unavailable, which raises ambiguity as to when in that broad time frame she may have fit diagnostic criteria for NF1.
Early onset hypertension represented another clue to underlying systemic disease; it is unusual for a patient this young to have a history of high blood pressure in the absence conventional cardiovascular risk factors such as smoking or obesity. Earlier recognition that the hypertension may have represented secondary hypertension could have prompted further investigation which would have included renovascular imaging. Earlier renovascular imaging may have identified the patient’s mid-aortic syndrome before presentation.
NF1-associated vasculopathy is well documented in literature, yet mid-aortic syndrome is rarely reported. A small number of case reports refer to a potential association between NF1 and mid-aortic syndrome [11–13]. Mid-aortic syndrome consists of narrowing of the thoracic or abdominal aorta. Our patient demonstrated severe abdominal aortic narrowing to 3 mm between the superior mesenteric and renal artery origins with established collateral circulation, suggesting chronic disease. Accounting for the presence of hypertension, café au lait macules, and other ambiguous symptoms including scoliosis, this case highlights the importance for clinicians to consider broader diagnoses such as NF1 or other connective tissue disorders in patients with mild or vague symptoms. For this patient, it was especially relevant given the family history and development of café-au-lait macules. This patient’s diagnosis of hypertension at an early age may have been a manifestation of her mid-aortic syndrome, as previously mentioned, which underlines the importance of investigating secondary causes in younger adults.
In conclusion, this case describes life-threatening haemorrhage in a patient with NF1 as her index presentation despite fulfilling current diagnostic criteria [2]. NF1 should be considered as a potential diagnosis in patients presenting with vasculopathies in the form of mid-aortic syndrome and other, more subtle, features of connective tissue disorders in the form of skeletal or cutaneous manifestations. Early diagnosis, especially in this case would allow patients access to genetic counselling, and follow-up by specialists.
Funding
None declared.
Conflicts of interest
None declared.
