Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report

Abstract

Abstract. Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple cafè-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease. IntroductionNeurofibromatosis type 1 (NF1) (MIM no. 162200), also known as von Recklinghausen disease, is clinically characterized by the presence of simple, diffuse and plexiform neurofibromas. Plexiform neurofibromas are unencapsulated, poorly-circumscribed tumors infiltrating the nerves and adjacent fat and muscles (1). The connective overgrowth can be limited to a single nerve or a plexus; in the latter case, when the plexus spreads to the epidermal and dermal tissues, it is termed molluscum fibrosum. This can occur multiple times, covering all body sites (including the forehead, temple, eyes, nape and upper lip) with the exception of the palms and soles (2). The plexiform neurofibroma variant, mixoglioma gelatiniforme, is usually soft and is located in the lower third of the leg, and when associated with lymphangiomatosis, it can give rise to elephantiasis neuromatosa (EN). EN is characterized by abnormal soft-tissue hypertrophy and bone dysplasia together with early and excessive bone growth of the affected leg compared with the contralateral leg (3,4). Pachidermocele or dermatholysis may be associated with NF1, showing an overlap of skin layers in the thorax, buttocks and roots of the limbs.The etiology of EN is not yet fully understood, but the association of primary lymphatic dysplasia with a lymphatic proliferative process has been proposed (5-7).The current study presents a case of NF1-associated EN with typical clinical manifestations. Written informed consent was obtained from the patient.

Desmoplastic Melanoma: A Challenge for the Oncologist

“…Recently, some authors reported a high incidence of NF1 mutations in DM, suggesting a central role for NF1 in the biology of this MM subtype [17,18]. NF1 is a GTPase-activating protein whose mutations are correlated to neurofibromatosis type 1 [19,20], but also to the development of several neoplasms, such as: glioma, neurofibroma, peripheral nerve sheath tumors, pheochromocytoma, breast cancer and lymphoma [21][22][23].…”

A Boot Brace for Elephantiasis Neuromatosa Associated with Neurofibromatosis Type 1

“…An association between lymphostasis and lymphedema with extensive hyperproliferation of soft tissues in EN has been suggested. 3,4 In the present case, both protection from injuries and continuous compression of the leg might have contributed to improvements in skin condition. We believe the double door–opening system could be optimal for these purposes.…”

“…This condition is termed elephantiasis neuromatosa (EN). 2–4 Changes in the vascular and lymphatic system, such as enlarged veins, 2 dilated lymphatics, 3 enlarged lymph nodes, 3,4 and dermal backflow, 4 have been observed in limbs enlarged by EN. Although surgery is the standard treatment for plexiform neurofibroma, 5 conservative treatment might be an option, especially for more complicated cases such as EN.…”

The concept of type 2 segmental mosaicism, expanding from dermatology to general medicine

“…Plexiform neurofibromas affecting a limb (Fig. ) are sometimes described as ‘elephantiasis neuromatosa’ . Moreover, T2SM may involve the brain, eye and orbita, bones and joints, parotis, thyroid, larynx, trachea, lung, heart, oesophagus, upper gastro‐intestinal tract (Fig.…”

“…2) are sometimes described as 'elephantiasis neuromatosa'. [34][35][36] Moreover, T2SM may involve the brain, 37 eye and orbita, [38][39][40] bones and joints, [41][42][43][44] parotis, 45 thyroid, 46 larynx, 47 trachea, 48 lung, 49 heart, 41,49,50 oesophagus, 51 upper gastro-intestinal tract ( Fig. 3), 49,52,53 rectum, 54,55 liver, 56,57 gall bladder, 58 pancreas, 56 retroperitoneum 59 and bladder.…”