Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report
- Authors:
- Published online on: April 19, 2016 https://doi.org/10.3892/ol.2016.4469
- Pages: 3709-3714
Abstract
Introduction
Neurofibromatosis 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.
Case report
Case history
In January 2014, the case of a female patient was brought to our attention at the Department of Dermatology of University of Modena and Reggio Emilia (Modena, Italy) due to a 29-year history of several neurofibromas and multiple (>6) cafè-au-lait macules. The patient presented with giant elephantiasis of the right leg, which had started to grow during late childhood, and had since accelerated its expansion in the following years (Fig. 1A). At birth, the patient exhibited a cafè-au-lait macule on the right thigh. By 1 year old, a semi-liquid mass had developed at the same site. The lesion was noticed by the parents and showed indolent growth with no signs of bleeding or pain. Upon histopathological examination, it presented with the aspects of a lymphangioma. Lymphedema of the ipsilateral foot and discrepant leg lengths were noted successively. In the following years, the uneven leg growth was associated with bone proliferation, which required a number of osteotomies with the aim of stopping the growth. Conventional lymphoscintigraphy (LS) was performed to assess the lower limb lymphatic drainage pathway.
The family history was suggestive of NF1, as the patient's father exhibited macrocephaly, hypertelorism, and multiple cafè-au-lait macules and neurofibromas.
Genetic testing, magnetic resonance imaging (MRI) and three-dimensional computed tomography (3D-CT) were also performed.
MRI and 3D-CT
The MRI and 3D-CT scan study showed a preponderance of adipose tissue in the elephantiasic limb, corresponding to three-quarters of its whole volume, in addition to a severe dorso-lumbar-sacral scoliosis with convexity on the left. Two central nervous system hamartomas of the pallidus nucleous were also identified by MRI. 3D-CT revealed a mild lumbo-sacral meningocele and giant L4 neurofibroma (Fig. 1B).
Germline mutation analysis of the NF1 gene
Genomic DNA was extracted from the peripheral blood of the patient and the patient's father using the QIAamp DNA Blood Mini kit (Qiagen Inc., Valencia, CA, USA), and stored at −20°C until use. All NF1 exons were amplified by polymerase chain reaction with intron spanning primers, as described previously (8), and then analyzed with denaturing high-performance liquid chromatography, as described previously (9). For each abnormal elution profile, genomic DNA was directly sequenced in each direction using a CEQ Dye-Terminator Cycle Sequencing kit (Beckman Coulter Inc., Miami, FL, USA) according to the manufacturer's instructions.
Mutations were checked using the Mutalyzer program (http://www.lovd.nl/mutalyzer). NF1 germline deletion g.129042_129043delAG; c.1541_1542del; p.(Gln514Argfs*43) was found in the proband and the patient's father. To the best of our knowledge, this type of mutation has not previously been described.
Lymphedema and limb lymphatic assessment
A common tape measure was used to assess the limb circumferences of the patient. Reference circumferences were the popliteal crease, point zero (K), +30 cm (A), +20 cm (B) and +10 cm (C) in the thigh, −10 cm (D), −20 cm (E) and −30 cm (F) in the lower leg, and 10 cm proximal from the tip of the first toe (G). Leg volumes were calculated according to these measurements (10).
Lower limb lymphatic function was assessed by LS, using injections of 37-MBq 99mTc-labeled human serum albumin. Injection points were in the first, second and fourth interdigital and retromalleolar spaces of the affected and contralateral foot. Image acquisition was obtained after 60 and 240 min using a dual head γ-camera (Philips Healthcare, Andover, MA, USA) equipped with a low-energy and high-resolution collimator, and an energy peak centered on 140 KeV (window of 20%).
The criteria to define lymphatic dysfunction include delay, asymmetric or absent visualization of regional lymph nodes, and the presence of dermal backflow. Other observations include the visualization of asymmetric lymphatic channels, collateral lymphatic channels, interrupted vascular structures, and lymph nodes of the deep lymphatic system (i.e., popliteal lymph nodes following web space injection in the lower extremities) (11).
In LS, the images obtained 60 min after the injections showed bilateral lower limb lymph flow delay. Mild dermal backflow in the absence of tracer migration was observed in the affected lower limb, whilst one inguinal lymph node was observed in the left limb. Posterior images confirmed the findings, also visualizing a popliteal lymph node in the healthy (left) leg. Images acquired at 240 min showed significant dermal backflow in the right limb, and hyperplasia and hypertrophy of the inguinal and external iliac lymph nodes, in comparison to those of the left leg (Fig. 1C).
Treatment and patient outcome
In May 2014, the patient was treated with surgery to reduce the volume of tissue in the leg region; tissue with a mass of 4.3 kg was removed. However, the outcome was not as good as expected due to hemorrhage during surgery, which prevented complete exision. Following surgery, the patient exhibited limited functional improvement and limb lightening. The patient was subsequently administered anticoagulant therapy with enoxaparin (8,000 IU, daily for one year) and underwent regular follow up examinations every three months for the first year and every six months subsequently. At the time of writing, the patient was well with a good prognosis.
Discussion
EN is a rare clinical manifestation associated with the NF1 phenotype. The condition should be defined as early and excessive growth in the width and length of the affected limb due to a neoplastic proliferation of the perineural connective tissue, together with congenital lymphatic insufficiency and chronic hyperemia. While no more than 30 cases are described in the literature (Table I) (12–32), the real incidence is estimated to be higher. The clinical expression is characterized by plexiform neurofibromas located in the superficial or deep nervous system associated with congenital lymphangiomathosis. Signs usually appear during the first years of life, due to lymphostasis and subsequent lymphedema causing adipocyte metaplasia of the adjacent tissues and chronic hyperemia inducing bone overgrowth and focal gigantism (34).
Distinct superficial dysplastic skin alterations known as pachidermocele or dermatholysis, histologically corresponding to mixoglioma gelatiniforme, must be distinguished from EN in patients affected by NF1 (2).
To date, little evidence is available regarding the role of lymphatic alterations in the pathogenesis of EN.
Based on the bilateral lymphatic defect, the presence of a primary lymphatic disease in the current NF1 patient can be hypothesized. The disease is probably supported by a dysplastic-hypertrophic condition as a result of a congenital alteration of the lymphatic network (35,36).
Regarding the lymph to fat transformation, it is known that lymphostasis due to primary and secondary lymphedema determines the transformation of fat cells, resulting in hypertrophied adipose tissue. Several studies (37–39) have suggested that lymphedema leads to adipose tissue accumulation and fibrosis. Moreover, we believe that this process is amplified in NF1 and in EN due to a primary lymphatic disorder, which is at the base of the clinical manifestation induced by the plexiform neurofibroma growth.
Overall, the diagnostic criteria for NF can be improved by the introduction and application of novel criteria based on a wider case series (EN, focal gigantism, mixoglioma gelatiniforme and primary lymphatic disorder), leading to the early diagnosis of NF1, particularly in pediatric patients. LS and MRI can be efficacious tools in the diagnosis and clinical characterization of early onset cutaneous, subcutaneous and skeletal anomalies.
Acknowledgements
The authors would like to thank Dr Federica Arginelli for providing useful comments.
Glossary
Abbreviations
Abbreviations:
NF1 |
neurofibromatosis type 1 |
EN |
elephantiasis neuromatosa |
LS |
lymphoscintigraphy |
MRI |
magnetic resonance imaging |
3D-CT |
three-dimensional computed tomography |
References
Bano S, Prasad A, Yadav SN, Chaudhary V and Sachdeva N: Elephantiasis neuromatosa of the lower limb in a patient with neurofibromatosis type-1: A case report with imaging findings. J Pediatr Neurosci. 5:59–63. 2010. View Article : Google Scholar : PubMed/NCBI | |
Pollock G: Report of a case of molluscum fibrosum or fibroma with observations. Med Chir Trans. 56:255–266. 1873. View Article : Google Scholar : PubMed/NCBI | |
Serradell AP: Neurocutaneous syndromes. Medicine - Programa de formación médica continuada acreditado. 8:5532–5547. 2003.(In Spanish). View Article : Google Scholar | |
Ponti G, Martorana D, Pellacani G, Ruini C, Loschi P, Baccarani A, De Santis G, Pollio A, Neri TM, Mandel VD, et al: NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies. Anticancer Res. 34:3021–3030. 2014.PubMed/NCBI | |
Flanagan BP and Helwing EB: Cutaneous lymphangioma. Arch Dermatol. 113:24–30. 1977. View Article : Google Scholar : PubMed/NCBI | |
Foeldi M: The role of the lymphatic circulation in the fluid circulation of the eye and the central nervous system. Arch Kreislaufforsch. 41:186–212. 1963.PubMed/NCBI | |
Lohrmann C, Pache G, Felmerer G, Foeldi E, Schaefer O and Langer M: Posttraumatic edema of the lower extremities: Evaluation of the lymphatic vessels with magnetic resonance lymphangiography. J Vasc Sur. 49:417–423. 2009. View Article : Google Scholar | |
De Luca A, Bottillo I, Dasdia MC, Morella A, Lanari V, Bernardini L, Divona L, Giustini S, Sinibaldi L, Novelli A, et al: Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. J Med Genet. 44:800–808. 2007. View Article : Google Scholar : PubMed/NCBI | |
De Luca A, Buccino A, Gianni D, Mangino M, Giustini S, Richetta A, Divona L, Calvieri S, Mingarelli R and Dallapiccola B: NF1 gene analysis based on DHPLC. Hum Mutat. 21:171–172. 2003. View Article : Google Scholar : PubMed/NCBI | |
International society of lymphology: The diagnosis and treatment of peripheral lymphedema. 2009 consensus document of the international society of lymphology. Lymphology. 42:51–60. 2009.PubMed/NCBI | |
Pecking AP: Possibilities and restriction of isotopic lymphography for the assessment of therapeutic effects in lymphedema. Wien Med Wochenschr. 149:105–106. 1999.PubMed/NCBI | |
Spittel RL and Fernando SE: A case of elephantiasis neuromatosa. Br Med J. 1:596–597. 1929. View Article : Google Scholar : PubMed/NCBI | |
Westcott RJ and Ackerman LV: Elephantiasis neuromatosa; a manifestation of von Recklinghausen's disease. Arch Derm Syphilol. 55:233–241. 1947. View Article : Google Scholar : PubMed/NCBI | |
Lenson N: Neurofibromatosis; a case report of elephantiasis neuromatosa of the right lower extremity, with invasion of the popliteal artery. AMA Arch Surg. 73:279–284. 1956. View Article : Google Scholar : PubMed/NCBI | |
Fethiere W, Carter HW and Sturim HS: Elephantiasis neuromatosa of the penis. Light and electron microscopical studies. Arch Pathol. 97:326–330. 1974.PubMed/NCBI | |
Yaghmai I and Tafazoli M: Massive subperiosteal hemorrhage in neurofibromatosis. Radiology. 122:439–441. 1977. View Article : Google Scholar : PubMed/NCBI | |
Sty JR, Starshak RJ and Woods GA: Neurofibromatosis: Lymphoscintigraphic observations. Clin Nucl Med. 6:264–265. 1981. View Article : Google Scholar : PubMed/NCBI | |
Harris WC Jr, Alpert WJ and Marcinko DE: Elephantiasis neuromatosa in von Recklinghausen's disease. A review and case report. J Am Podiatry Assoc. 72:70–72. 1982. View Article : Google Scholar : PubMed/NCBI | |
Holck S, Medgyesi S, Darre E and Lassen M: Elephantiasis neuromatosa. A light, immunohistochemical and electron microscopic study. Virchows Arch A Pathol Anat Histopathol. 404:427–434. 1984. View Article : Google Scholar : PubMed/NCBI | |
Birch PD and Davies AM: The value of computed tomography in elephantiasis neuromatosa. Br J Radiol. 61:76–78. 1988. View Article : Google Scholar : PubMed/NCBI | |
Hertzanu Y, Hirsch M, Peiser J and Avinoach I: Computed tomography of elephantiasis neuromatosa. J Comput Assist Tomogr. 13:156–158. 1989. View Article : Google Scholar : PubMed/NCBI | |
Bardelli AM and Hadjistilianou T: Buphthalmos and progressive elephantiasis in neurofibromatosis. A report of three cases. Ophthalmic Paediatr Genet. 10:279–286. 1989. View Article : Google Scholar : PubMed/NCBI | |
Kuo LA and Kuo RS: Plexiform neurofibromatosis: A difficult surgical problem. Aust N Z J Surg. 60:732–735. 1990. View Article : Google Scholar : PubMed/NCBI | |
Roy SM and Ghosh AK: Elephantiasis neuromatosa: A clinicopathologic study of four cases. J Ind Med Assoc. 90:185–187. 1992. | |
Kokandkar HR, Vyas AS, Kumbhakarna NR and Totala RJ: Congenital plexiform neurofibroma with a sarcomatous nodule in a three month old child. Indian J Cancer. 31:130–132. 1994.PubMed/NCBI | |
Münte TF, Matzke M, Johannes S, Dietrich B and Dengler R: MRI of elephantiasis neuromatosa. J Neurol. 243:6191996. View Article : Google Scholar : PubMed/NCBI | |
Stevens KJ, Ludman CN, Sully L and Preston BJ: Magnetic resonance imaging of elephantiasis neuromatosa. Skeletal Radiol. 27:696–701. 1998. View Article : Google Scholar : PubMed/NCBI | |
Akyol M, Ozçelik S, Marufihah M and Elagöz S: Elephantiasis neuromatosa and Becker's melanosis. J Dermatol. 26:396–398. 1999.PubMed/NCBI | |
Lorberboym M, Trejo L and Lampl Y: Bone scintigraphy of elephantiasis neuromatosa in Von Recklinghausen's disease. Clin Nucl Med. 25:812–813. 2000. View Article : Google Scholar : PubMed/NCBI | |
Steenbrugge F, Poffyn B, Uyttendaele D, Verdonk R and Verstraete K: Neurofibromatosis, gigantism, elephantiasis neuromatosa and recurrent massive subperiosteal hematoma: A new case report and review of 7 case reports from the literature. Acta Orthop Belg. 67:168–172. 2001.PubMed/NCBI | |
Hourani R, Rizk T, Kung S and Boudghène F: Elephantiasis neuromatosa in neurofibromatis type I. MRI findings with review of the literature. J Neuroradiol. 33:62–66. 2006. View Article : Google Scholar : PubMed/NCBI | |
Martínez-García S, Vera-Casaño A, Eloy-García Carrasco C, del Boz-González J, Martínez-Pilar L and Crespo-Erchiga V: Elephantiasis neuromatosa in a patient with neurofibromatosis type 1. J Eur Acad Dermatol Venereol. 22:103–105. 2008. View Article : Google Scholar : PubMed/NCBI | |
Hoshi M, Ieguchi M, Taguchi S and Yamasaki S: A case report of surgical debulking for a huge mass of elephantiasis neuromatosa. Rare Tumors. 1:e112009. View Article : Google Scholar : PubMed/NCBI | |
Holt JF: 1977 Edward B. D. Neuhauser lecture: Neurofibromatosis in children. AJR AM J Roentgenol. 130:615–639. 1978. View Article : Google Scholar : PubMed/NCBI | |
Liu NF, Yan ZX and Wu XF: Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography. Eur J Vasc Endovasc Surg. 44:345–349. 2012. View Article : Google Scholar : PubMed/NCBI | |
Preston JM, Starshak RJ and Oechler HW: Neurofibromatosis: Unusual lymphangiographic findings. AJR Am J Roentgenol. 132:474–476. 1979. View Article : Google Scholar : PubMed/NCBI | |
Ryan TJ: Lymphatics and adipose tissue. Clin Dermatol. 13:493–498. 1995. View Article : Google Scholar : PubMed/NCBI | |
Rosen ED: The molecular control of adipogenesis, with special reference to lymphatic pathology. Ann N Y Acad Sci. 979:143–158; discussion 188–196. 2002. View Article : Google Scholar : PubMed/NCBI | |
Brorson H: Liposuction normalizes-in contrast to other therapies-lymphedema-induced adipose tissue hypertrophy. Handchir Mikrochir Plast Chir. 44:348–354. 2012.PubMed/NCBI |