Painful Swelling in a Case of Neurofibromatosis 1: An Intriguing Entity

Dear Editor, Neurofibromatosis 1 (NF1) is an inherited neurocutaneous disorder characterized by the presence of multisystem tumors throughout the skin and central nervous system (CNS), which carries a risk of malignant transformation. Patients with NF1 may present with sudden onset painful swelling due to development of malignant peripheral nerve sheath tumor (MPNST), elephantiasis neuromatosa (EN), and vascular malformations. We report a rare association of NF1 with venous malformation in a 13-year-old female child. A 13-year-old female born to non-consanguineous parents presented to us with multiple dark-colored lesions on the body since birth and painful swelling over the right lower limb for the past 1 year. Her father had multiple café-au-lait spots and neurofibromas with single plexiform neurofibroma over the upper back. There was no history of pruritus, learning disabilities, or decreased visual acuity. On cutaneous examination, there were multiple café-au-lait macules [Figure 1a], predominantly on the trunk with bilateral axillary (Crowe's sign) [Figure 1b] and palmar freckling (Patrick Yesudian sign) [Figure 1c]. There was a single grayish-black, tender swelling over the posteromedial aspect of the right thigh and leg [Figure 1d]. On palpation, thrill was absent and bruit could not be auscultated. Also, there was no local rise of temperature. The length and girth of the right lower limb were more than those of the left (length >5 cm, girth >3 cm at the level of midthigh) with anterior bowing of the right tibia [Figure 2a]. Varicosities were also present over the right leg [Figure 2b]. Ophthalmic examination revealed the absence of Lisch nodules. Rest general and systemic examination findings were normal. On history and clinical examination, a differential diagnoses of NF1 with malignant peripheral nerve sheath tumor (MPNST), venous malformation, elephantiasis neuromatosa (EN), and Klippel Trenaunay syndrome (KTS) were considered. The radiograph of the bilateral lower limbs revealed an abnormal increase in soft tissue shadow in the right thigh and leg with anterior bowing of the right tibia. Doppler of the bilateral lower limbs was suggestive of diffuse tortuous dilated venous vascular channels with thrombosis in the subcutaneous and intramuscular planes of the affected limb [Figure 3a and b]. Magnetic resonance imaging (MRI) confirmed the doppler findings and also revealed hypertrophy of the right lower limb due to hypertrophy of soft tissue, tibia, and bones of the right foot [Figure 4a-d]. Based on aforementioned findings, a diagnosis of NF1 with venous malformation was reached. Parents were counseled, and the patient was referred to a plastic surgeon and interventional radiologist for further management.Figure 1: (a) Café-au-lait spots over chest and abdomen (b). Axillary freckling (Crowe's sign) over right axilla (c). Bilateral palmar freckling (Patrick Yesudian sign) (d). Single grayish-black, tender swelling over posteromedial aspect of right thigh and legFigure 2: (a) The length (97 cm) and circumference at midthigh (33 cm) of right lower limb were greater than the length (92 cm) and circumference (30 cm) of left lower limb (b). Prominent varicosity of veins on back of right thighFigure 3: (a and b) Doppler reveals diffuse tortuous dilated venous vascular channels with thrombosis in the subcutaneous and intramuscular planes of right lower limb (yellow arrow)Figure 4: (a-d) Post-contrast T1FS MR: multiple dilated tortuous venous channels in subcutaneous and intermuscular planes along medial thigh (a and c) (yellow arrow). Contrast MRA: enhancement on venous phase (b) (white arrow). T1WI: dilated tortuous venous channels in right leg (d) (blue arrow)NF1 (Von Recklinghausen's disease) is an autosomal dominant disorder affecting approximately 1 in 3500 people. New onset painful swelling in NF1 is more likely related to hemorrhage and infarction in tumor, malignant transformation of plexiform neurofibromas (MPNST), EN, vascular malformation. MPNST can be differentiated by sudden growth of neurofibroma, sudden persistent severe pain, or change in consistency from soft to hard.[1] EN is defined as early and excessive growth in the width and length of the affected limb due to neoplastic proliferation together with congenital lymphatic insufficiency and chronic hyperemia. It is more or less indolent growth without signs of bleeding or pain. It usually appears during the first year of life due to lymphostasis and subsequent lymphedema, causing adipocyte metaplasia of adjacent tissue and chronic hyperemia, which leads to bony growth and gigantism.[2] Vascular malformation on the other hand affects small, medium, and large arteries and veins. Clinically, venous malformation is characterized by painful, soft, and compressible mass with the absence of palpable local thrill and bruit on auscultation and involves low-flow malformations on ultrasonography and MRI, as seen in our case. High-flow malformations are commonly arteriovenous malformations, with the presence of thrill and bruit clinically. Hence, a detail history, thorough clinical examination, relevant radiological investigations, and occasional histopathology are required to reach a proper diagnosis. The overall incidence of vascular malformations in NF1 is estimated to be between 0.4% and 6.4%. The vasculopathy is thought to arise from disruption of the critical role of neurofibromin in regulating the vascular endothelium smooth muscle cells, bone marrow cells with macrophage dysfunction resulting in neointimal hyperplasia, inflammation, and exaggerated response to injury including enhanced angiogenesis. The commonest vascular abnormalities associated with NF1 include renal artery stenosis (41%), cerebral vasculopathy (19%), and abnormalities of the abdominal aorta (12%).[3,4] However, our case had venous malformation with thrombosis in the right lower limb. Surgical treatment must be decided judiciously and individualized based on vasculopathy associated with NF1. Our case emphasizes the importance of careful clinical and proper radiological examination for the diagnosis of new onset swelling in NF1. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.