Dermatology Online Journal

Mosaic neurofibromatosis type 1
Christine Liang MD, Julie V Schaffer MD
Dermatology Online Journal 14 (5): 6

Department of Dermatology, New York University

---

Abstract

A 24-year-old man presented with numerous lentigines and multiple café-au-lait macules on both sides of the face, neck, and trunk as well as on the proximal area of the upper extremities and in the axillae. The pigmented lesions had a Blaschko-linear distribution on the upper trunk and were limited to the left side of the abdomen, with a sharp demarcation at the midline. Multiple, cutaneous neurofibromas were found on the trunk, and ophthalmologic examination showed a Lisch nodule in the left iris. The clinical findings and their widespread but segmental distribution were consistent with a diagnosis of mosaic neurofibromatosis type 1.

---

Clinical synopsis

A 24-year-old Nepalese man presented to the Dermatology Clinic at Bellevue Hospital Center for treatment of his acne. On discussion of his medical history, the patient also was aware of asymptomatic, pigmented spots on his face, torso, and upper extremities, which he had first noticed 5 years prior. He had no important past medical history and took no medications. No immediate family members had similar skin findings. Review of systems disclosed a 2-year history of low back pain.

Physical examination

On both sides of the face, neck, chest, and back as well as in the axillae and on the proximal area of the upper extremities were numerous, 2-3 mm, tan macules. The macules were present only on the left side of the abdomen, with a sharply-demarcated border at the midline. Clearly demarcated areas of sparing also were evident in the right posterior axilla and on the right side of the chest and back, which included some arched bands that followed the lines of Blaschko. Approximately ten, 1-2 cm, tan, café-au-lait macules were present on the neck, trunk, and arms and were limited to areas with small, tan macules. Scattered on the trunk were multiple, soft, pink, barely-elevated papules that invaginated with gentle pressure (buttonhole sign); a few of these lesions were located on the right side of the abdomen, where tan macules were not present. There were no lesions in the groin or on the lower extremities. Ophthalmologic evaluation showed a Lisch nodule of the left iris.

Figure 1	Figure 2

Laboratory data

None

Histopathology

None

Comment

Mosaic (segmental) neurofibromatosis type 1 (NF1) presents with the characteristic features of NF1 that are limited to one or more regions of the body. It is attributed to a somatic mutation in the NF1 gene. A somatic mutation that occurs late in embryologic development can result in disease that is localized to one segment, in contrast to an earlier mutation that may result in widespread disease (e.g., affecting multiple segments on both sides of the body) [1]. Patients such as ours, who have widespread involvement of mosaic NF1, often meet diagnostic criteria for classic NF1, and careful examination may be necessary to recognize the mosaic distribution of the skin lesions and avoid misdiagnosis [2]. One recent study documented somatic mosaicism in 8 of 20 patients (40%) with sporadic NF1 (presumably full-blown) that was attributed to a NF1 microdeletion [3]. Because of the clinical variability of NF, several classification systems have been proposed over the past few decades. In 1982, Riccardi divided NF into eight types based on clinical features and inheritance. Segmental NF or type 5 was defined as non-familial café-au-lait macules (or freckling) and neurofibromas limited to 1 side of the body without systemic involvement [4]. Recognition of cases not meeting these strict criteria led Roth to further divide segmental NF into 4 subsets: true segmental (meeting Riccardi's definition), localized cases with deep involvement, hereditary segmental NF, and bilateral segmental NF [5].

In 2001 Ruggieri and Huson proposed the terms mosaic generalized NF1 and mosaic localized (segmental) NF1 to reflect our current understanding of the genetic pathogenesis of segmental NF (specifying NF1 because mosaic NF2 can also occur); however, the area of involvement required to qualify as generalized was not defined [1, 6]. They further divided segmental NF1 into 4 groups as follows: pigmentary changes (café-au-lait macules and freckling) only, cutaneous neurofibromas only, pigmentary changes plus neurofibromas, and isolated plexiform neurofibromas. The skin lesions in traditional segmental NF1 are most often unilateral but can be bilateral in as many as one-third of patients [1]. In patients with pigmentary involvement only, the distribution tends to follow the lines of Blaschko, and NF1 mutations have been detected in fibroblasts from affected skin (but not unaffected skin or peripheral blood leukocytes) [7]. In contrast, patients with segmental NF1 who present with neurofibromas only typically have lesions in a dermatomal distribution, and their NF1 mutations appear to be limited to Schwann cells [8]. Similar to non-mosaic NF1, pigmentary changes and plexiform neurofibromas usually become apparent during early childhood, whereas cutaneous neurofibromas typically arise in adolescence and adulthood. However, many patients with segmental café-au-lait macules and freckling never develop neurofibromas. Most patients with segmental NF1 do not have systemic involvement although extracutaneous manifestations, such as learning difficulties, visceral neurofibromas, skeletal abnormalities, and optic pathway tumors, have been reported [1, 9]. Lisch nodules are uncommon in segmental NF1; in two large series, they were observed in only in 4 of 155 patients (2.5%) [1, 10]. Rarely, patients with segmental NF1 have had offspring with full-blown NF1, which is thought to be a result of gonadal mosaicism [9]. This risk is small, and it is thought to be proportional to the percentage of body area affected [1]. Patients with mosaic forms of NF1 should undergo thorough physical examination, which includes ophthalmologic evaluation, examination of first-degree relatives, and appropriate genetic counseling.

References

1. Ruggieri M, Huson S. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurol 2001;56:1433

2. Vandenbroucke I, et al. Genetic and clinical mosaicism in a patient with neurofibromatosis type 1. Hum Genet 2004;114:284

3. Kehrer-Sawatzki H, et al. High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet 2004;75:410

4. Riccardi VM. Neurofibromatosis: clinical heterogeneity. Curr Probl Cancer 1982;7:1

5. Roth RR, et al. Segmental neurofibromatosis. Arch Dermatol 1987;123:917

6. Ruggieri M, Huson S. Mosaic (segmental) neurofibromatosis type 1 and type 2: no longer neurofibromatosis type 5. Am J Med Genet 2001;101:178

7. Tinschert S, et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 2000;8:455

8. Redlick F, et al. Segmental neurofibromatosis follows Blaschko's lines or dermatomes depending on the cell line affected: case report and literature review. J Cut Med Surg 2004;8:353

9. Gonzalez G, et al. Bilateral segmental neurofibromatosis: a case report and review. Pediatr Neurol 2007;36:51

10. Listernick R, et al. Segmental neurofibromatosis in childhood. Am J Med Genet 2003;121:132

© 2008 Dermatology Online Journal