Lower Extremity Skin Ulcer Associated With Neurofibromatosis Type 1: A Case Report

Case Report and Brief Review

Lower Extremity Skin Ulcer Associated With Neurofibromatosis Type 1: A Case Report

Keywords

October 2019

ISSN 1943-2704

Index Wounds 2019;31(10):E65–E67

The authors present the case of a 32-year-old man with a painful ulcer on his left thigh of 3 weeks’ duration in the same location as a long-time capillary malformation associated with alopecia.

Abstract

Introduction. The association between neurofibromatosis type 1 (NF-1) and vasculopathy has been reported frequently, especially cerebral, intestinal, and peripheral vasculopathy. However, cutaneous vasculopathy is infrequent. Case Report. The authors present the case of a 32-year-old man with a painful ulcer on his left thigh of 3 weeks’ duration in the same location as a long-time capillary malformation associated with alopecia. The skin biopsy showed signs of perivascular fibromuscular dysplasia with proliferating myofibroblastic cells. The patient had been treated with various therapeutic options, such as topical antibiotics, oral and intralesional corticosteroids, and oral cyclosporine and intravenous prostanoids. Conclusions. Cutaneous vasculopathy related to the skin, such as livedo reticularis and ulcers of torpid evolution due to cutaneous vasculopathy are extremely rare. Thus, it is necessary to include skin ulcers as one of the phenotypic manifestations of NF-1.

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Introduction

Neurofibromatosis type 1 (NF-1), is an autosomal-dominant genodermatosis caused by mutations in the NF-1 gene at chromosome 17q11.2.¹ Café-au-lait macules, neurofibromas, skeletal dysplasia, and learning disability are its most frequent and known phenotypic features.¹ The association between NF-1 and vasculopathy has been reported frequently, especially cerebral, intestinal, and peripheral vasculopathy. However, cutaneous vasculopathy is infrequent.¹ In this article, the authors present the case of a Spanish man with NF-1 who developed a therapy-resistant skin ulcer on his leg as well as a review of other cases published in the literature.

Case Report

A 32-year-old man was admitted to the Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain) with complaints of a painful ulcer on his left thigh of 3 weeks’ duration. He had been diagnosed with NF-1 27 years prior and had suffered from hypoplasia of his left leg since childhood. The patient described having had similar lesions previously in the same location as a capillary malformation associated with alopecia lasting since he was 8 years old.

Physical exploration at presentation revealed an ulcer measuring 8 cm x 6 cm on his left thigh with purple edges and eschar. In addition, there was a discrepancy in the length of his leg and a well-defined reticulate patch of red to purple skin with alopecia on the thigh that had symmetrical distribution (Figure 1A). Doppler scanning detected normal pulses and various imaging tests (magnetic resonance and angiography) were performed but did not show significant findings.

The remainder of the supplementary tests (blood count, biochemistry, coagulation, serology, and autoimmunity) did not present alterations. However, the skin biopsy showed signs of perivascular fibromuscular dysplasia and moderate fibrosis of the stroma with thickened walls and proliferating myofibroblastic cells (Figure 1B).

At that point in time, the patient had been treated with various therapeutic options such as topic antibiotics, oral and intralesional corticosteroids (0.5 mg/kg/day), and oral cyclosporine (4 mg/kg/day) and intravenous prostanoids that resulted in the ulcer measuring 2.3 cm x 1.5 cm 3 months after the start of treatment (Figure 1C).

Discussion

Vascular complications in NF-1 are well described in the literature, and it is well known that major cardiac and cerebral vessels are the most affected in causing a high mortality. Though complications related to the skin, such as livedo reticularis and ulcers of torpid evolution due to cutaneous vasculopathy, are extremely rare, underestimated, and poorly recognized. Therefore, statistical data on their frequency are unknown.¹

Vascular involvement in NF is probably due to an impaired neurofibromin function. This protein would act as a tumor suppressor, inhibiting the ras-extracellular signal-regulated kinase signaling pathway. Mutation of the neurofibromin gene would cause an alteration of vascular histogenesis from a proliferation of smooth muscle cells of the vessels.¹

The Table summarizes the only 4 cases^2-5 the authors found in the literature. They are usually indolent skin ulcers, with poor therapeutic response, located in the proximal part of both the upper and lower extremities, with most cases described between the second and fourth decades of life (28–42 years). Another risk factor that must be quantified is the presence of hypoplasia in the limbs and/or capillary malformation.

Differential diagnosis with large-vessel affection is crucial, in which a lower pulse would be evidenced by Doppler scanning and the angiography presents alterations in the vessel caliber. Biopsy is required for the diagnosis of cutaneous vasculopathy, which shows an alteration of the vessel wall from the deep dermis and hypodermis.

There has been poor therapeutic response of different treatments that have been tried (eg, prednisolone, cyclosporine, steroids, mycofenolate mofetil dapsone, steroids, cyclophosphamide bolus therapy, and infliximab).^2-4However, Khelifa et al⁵ found improvement with using imatinib in their patient.

Conclusions

This paper reports a case in which an ulcer due to cutaneous vasculopathy coalesces in an area with capillary malformation and alopecia; this association has not been previously reported. When clinicians encounter a patient with NF-1 and skin ulcers, they should make a broad differential diagnosis highlighting the importance of including cutaneous vasculopathy as a phenotypic manifestation of NF-1.

Acknowledgments

Authors: Tamara Gracia-Cazaña, PhD¹; Sonia de la Fuente, MD²; María A Concellón, MD³; and Mariano Ara-Martín, MD, PhD³

Affiliations: ¹Department of Dermatology, Hospital de Barbastro, Huesca, Spain; ²Department of Dermatology, Hospital Ernest Lluch, Calatayud, Zaragoza, Spain; and ³Department of Dermatology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

Correspondence: Tamara Gracia-Cazaña, PhD, Department of Dermatology, Hospital de Barbastro, Huesca. Av Pirineos nº 11 1ºA, P.O. Box: 22011, Barbastro, Huesca, Spain; tamgracaz@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.

References

1. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and 2. JAMA. 1997;278(1):51–57. 2. Ljunggren B, Holst R, Simanaitis M, Rausing A. Skin ulcerations as manifestation of vasculopathy in neurofibromatosis. J Am Acad Dermatol. 2004;51(4):656–659. 3. Obermoser G, Zelger BG, Millonig G, Sepp N, Vogel W, Zelger B. Vasculopathy in von Recklinghausen’s neurofibromatosis--a diagnostic quandary. J Am Acad Dermatol. 2004;50(5 Suppl):S107–S109. 4. Fujimura T, Okuyama R, Aiba S. Therapy-resistant skin ulcers on hypoplastic leg associated with neurofibromatosis type 1. J Dermatol. 2008;35(2):120–121. 5. Khelifa I, Saurat JH, Prins C. Use of imatinib in a patient with cutaneous vasculopathy in the context of von Recklinghausen disease/neurofibromatosis [published online November 12, 2014]. Br J Dermatol. 2015;172(1): 253–256.