Neurofibromatosis with vitiligo: an uncommon association rather than coexistence?☆☆☆

ype 1 neurofibromatosis (NF1) is an autosomal domiant multisystem disease caused by a mutation in the eurofibromin 1 gene which affects tissues derived from he neural crest.1 Clinically, it is characterized by a pectrum of defects comprising of neural tumors, cafe-auait spots, intertriginous freckling, and skeletal defects. eneralized vitiligo has rarely been reported with neuofibromatosis. Here, we present two cases of NF1 ssociated with vitiligo and showing the halo phenomenon in eurofibromas. A 28-year-old male patient who was a known case f NF1 presented with multiple depigmented patches on he skin, which had started developing in the last four ears. His family history revealed that his mother also ad neurofibromatosis, with no history of any depigmented esions. Dermatological examination revealed multiple wellemarcated, light-brown macules of size varying from 5 o 50 mm present over the trunk, back, and upper limbs. umerous sessile as well as pedunculated dome-shaped apulonodular lesions of varying sizes, suggestive of neuofibromas, were present over the face, trunk, back, and pper limbs. Some of these lesions were encircled by a epigmented halo. Sharply defined depigmented patches, onsistent with a diagnosis of vitiligo and varying between and 7 cm in size, were present over back, elbows, and orsum of hands and feet (Fig. 1). Bilateral axillary frecking was also seen. Slit lamp examination of iris showed the resence of Lisch nodules. Dermoscopy of the vitiligo lesion howed reduced pigmentary network as compared to normal kin (Fig. 2). The second case was a 35-year-old male patient; a known ase of neurofibromatosis presented with depigmented brother. On cutaneous examination, multiple dome-shaped, skin colored papulonodular lesions of variable sizes and soft in consistency were present over the face, trunk, back, and extremities. Some nodules had depigmented halo around them. Multiple well-demarcated, light brown colored patches, 5--20 mm in size, were present over back, chest and upper extremities. Sharply demarcated patches of depigmentation suggestive of vitiligo, along with freckles, were present in both the axilla and over the trunk and


Dear Editor,
Type 1 neurofibromatosis (NF1) is an autosomal dominant multisystem disease caused by a mutation in the neurofibromin 1 gene which affects tissues derived from the neural crest. 1 Clinically, it is characterized by a spectrum of defects comprising of neural tumors, cafe-aulait spots, intertriginous freckling, and skeletal defects. Generalized vitiligo has rarely been reported with neurofibromatosis. Here, we present two cases of NF1 associated with vitiligo and showing the halo phenomenon in neurofibromas.
A 28-year-old male patient who was a known case of NF1 presented with multiple depigmented patches on the skin, which had started developing in the last four years. His family history revealed that his mother also had neurofibromatosis, with no history of any depigmented lesions. Dermatological examination revealed multiple welldemarcated, light-brown macules of size varying from 5 to 50 mm present over the trunk, back, and upper limbs. Numerous sessile as well as pedunculated dome-shaped papulonodular lesions of varying sizes, suggestive of neurofibromas, were present over the face, trunk, back, and upper limbs. Some of these lesions were encircled by a depigmented halo. Sharply defined depigmented patches, consistent with a diagnosis of vitiligo and varying between 2 and 7 cm in size, were present over back, elbows, and dorsum of hands and feet (Fig. 1). Bilateral axillary freckling was also seen. Slit lamp examination of iris showed the presence of Lisch nodules. Dermoscopy of the vitiligo lesion showed reduced pigmentary network as compared to normal skin (Fig. 2).
The second case was a 35-year-old male patient; a known case of neurofibromatosis presented with depigmented patches involving the normal skin and the skin surrounding the neurofibromas over the previous year. There was a family history of neurofibromatosis in his father and ଝ How to cite this article: Tandon S, Singh A, Arora P, Gautam RK. Neurofibromatosis with vitiligo: an uncommon association rather than coexistence? An Bras Dermatol. 2019;94:624---6. ଝଝ Study conducted at the Dermatology Department, Dr. Ram Manohar Lohia Hospital, New Delhi, India.
brother. On cutaneous examination, multiple dome-shaped, skin colored papulonodular lesions of variable sizes and soft in consistency were present over the face, trunk, back, and extremities. Some nodules had depigmented halo around them. Multiple well-demarcated, light brown colored patches, 5---20 mm in size, were present over back, chest and upper extremities. Sharply demarcated patches of depigmentation suggestive of vitiligo, along with freckles, were present in both the axilla and over the trunk and   NF1 is one of the most common autosomal dominant neurocutaneous disorder, with an estimated prevalence of around 1 in 3500 individuals. It has a highly variable clinical expression and approximately 30---50% of all patients lack a family history of the disease, representing de novo mutations of the NF1 gene.
Friedrich Von Recklinghausen was the first to describe the classical features of the disease and pointed out that the origin of the skin tumor was from peripheral nerves. Café-au-lait macules (CALMs) which are the first sign of NF1, signify the collection of heavily pigmented melanocytes originating from the neural crest in the epidermis. Ninetyfive percent of patients of NF1 have CALMs by the time they reach the adulthood. Regarding the pigmentary changes, it was suggested that since the pigment producing melanocyte originates in the neural crest, the presence of pigmentary lesions due to changes in melanocyte cell growth and differentiation can be expected. Cell culture studies have shown that the NF1 gene defect affects melanogenesis in the epidermal melanocytes of NF1 patients, resulting in the various hyperpigmentary changes seen in NF1. 2 The halo phenomenon signifies the sudden development of a depigmented halo around a congenital nevus, Spitz nevus, blue nevus, neurofibromas, and malignant melanomas. Shin et al. 3 described a case of naevus combined with vitiliginous changes and speculated that the immunological process involved in vitiligo simultaneously affected the underlying dermal naevus cells, causing their degeneration. Gach et al. 4 pointed out that clinical and histological similarity between the congenital melanocytic nevi and neurofibromas was because of the fact that both melanocytes and Schwann cells originate from the neural crest (Table 1). The levels of chronically activated CD8 + T-cells are increased in NF1 patients, which provides further evidence that the halo phenomenon in neurofibromas in the pres-ence of generalized vitiligo develops as an immunological response. 5 A thorough review of the literature yielded the following cases of neurofibromatosis associated with vitiligo as described in table 1. The sudden appearance of the halo phenomenon in patients of neurofibromatosis should not be treated as a mere co-existence, but as a marker of a much more sinister association between neurofibromatosis and vitiligo. We recommend that further studies should be carried out to provide a greater insight into this complex association.

Financial support
None declared.

Author's contribution
Sidharth Tandon and Pooja Arora: Approval of the final version of the manuscript; elaboration and writing of the manuscript; critical review of the literature; critical review of the manuscript.
Ajeet Singh: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing and interpreting the data; effective participation in research orientation; critical review of the literature; critical review of the manuscript.
Ram Krishan Gautam: Critical review of the literature; critical review of the manuscript.

Conflicts of interest
None declared.

Dear Editor,
We report the case of a 24-year-old female, Fitzpatrick phototype V, referred to our Dermatology Department for an asymptomatic mass in her left dorsal region. The patient reported a slow growth of this mass over several years. Physical examination revealed a palpable, soft, subcutaneous tumor in the left dorsal region, without apparent involvement of the superjacent skin, which was painless on palpation. The remainder of the examination was otherwise normal.
A high-resolution thoracic computed tomography performed one year before, in the context of an episode of asthma exacerbation, had revealed a large, lowdensity, subcutaneous nodularity in the referred topography (Fig. 1A). Also, an ultrasound-guided core needle biopsy (Fig. 1B)of this well-defined, slightly hyperechoic, subcutaneous mass identified a neoplasm of globular cells, some with multi-vacuolated cytoplasm and others with granular, eosinophilic cytoplasm, without nuclear atypia.
Considering this, we performed a complete surgical tumor resection, under local anesthesia, in an uneventful procedure ( Fig. 2A). The tumor measured approximately 60 × 50 × 20 mm, had a gelatinous external surface and, on section, showed a soft consistency and a brownish coloration ( Fig. 2A and B). The histopathological examination revealed a hypodermic tumor, involved by a thin fibrous capsule, constituted by adipocytes with granular, eosinophilic cytoplasm, without cytologic atypia, numerous multi-vacuolated adipocytes and some uni-vacuolated cells, establishing the definite diagnosis of a hibernoma (Fig. 3). The patient recov- Hibernomas are rare, benign soft-tissue tumors arising from vestigial brown fat, which can be located in the subcutaneous tissue, the skeletal muscle, or the intermuscular fascia. 1,2 There are four histological variants of hibernoma: typical (82%), myxoid (9%), lipoma-like (7%), and spindle-cell (2%). 1 Hibernomas vary in size (1---24 cm, average dimension 9.3 cm) and location, occurring most commonly in the thigh, peri-and interscapular region, neck, arm, abdominal cavity, and retroperitoneum, and they are typically highly vascularized. 1,3---5 They are most often diagnosed in adults (mean age 38 years). 1 These lipomatous tumors generally present either as slow-growing, painless, soft, palpable and mobile masses, or as incidentalomas in imaging studies. 1,3---5 Symptoms secondary to compression of adjacent structures can also develop due to their growth. 1,3,4 Differential diagnosis is not always straightforward, and includes not only benign soft-tissue neoplasms (like atypical lipomas, hemangiomas, and angiolipomas) but also malignant, aggressive tumors (namely well-differentiated liposarcomas, myxoid liposarcomas, and rhabdomyosarcomas). 1,2 In fact, hibernomas can mimic these other tumors clinically, imagiologically, and even histologically, considering some similar features in biopsy specimens. 1---5 Histopathological examination of the tumor following complete surgical excision, which is curative, is essential for confirming the diagnosis. 1,4,5 Financial support None declared.

Author's contribution
Margarida Moura Valejo Coelho: Approval of the final version of the manuscript; elaboration and writing of the manuscript; obtaining, analyzing and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct