Segmental form of mosaic neurofibromatosis 1

The case

A healthy 16-year-old girl presented with asymptomatic lesions she had at birth. Examination revealed a 15 cm well-demarcated light brown hyperpigmented background patch localized to the right inguinal skin-fold and, within it, café-au-lait macules and patches, greater than 1.5 cm, with diffuse freckling (Figure 1).

Figure

Diagnosis: Classic segmental form of mosaic neurofibromatosis (MNF1)

Etiology/epidemiology

NF1 is the most common form of neurofibromatosis, with an estimated prevalence of 1 in 4500, although the mosaic form has a prevalence of 1 in 36,000-40,000, but is likely to be underreported.¹ The skin condition MNF1 occurs after microdeletion mutations in the NF1 gene during embryonic development. Skin involvement can range from a narrow segment to half of the body in either symmetrical or asymmetrical distribution, depending on the timing of the mutation and the cell lines affected.²

Clinical Findings

Patients with MNF1 may meet the diagnostic criteria for NF1, but their findings occur in more localized areas as in our patient. Diagnosis is made using the National Institutes of Health criteria based on the presence of at least 2 clinical findings, of which our patient has 6 or more café-au-lait macules or patches (greater than 0.5 cm in children or 1.5 cm in adults) and freckling in the inguinal crease.³ However, children with only 3-5 café-au-lait lesions could also be affected by MNF1, though these cases are often underreported. For this presentation, the natural progression of MNF1 is similar to that of NF1, with patients first presenting with café-au-lait lesions, followed by freckling. A classic sign seen in our patient is a subtle hyperpigmented background patch in the affected area. Other diagnostic criteria include 2 or more neurofibromas or one plexiform neurofibroma, two or more Lisch nodules, optic glioma, bony dysplasia, or a first-degree relative with NF1. When they arise, neurofibromas are usually seen in adulthood.

Complications seen in NF1 include hypertelorism, macrocephaly, short stature, and thorax abnormalities, as well as learning disabilities, ophthalmologic and orthopedic issues, and increased risk of certain malignancies.^1,3 However, among MNF1 with localized skin involvement, complications are more rare, but have been reported to occur, especially with larger involvement of the skin, though not necessarily in the same location as skin involvement.¹

Differential diagnosis

About 10% of the general population has 1 to 2 café-au-lait lesions, which can be normal.³ Other important differential diagnoses include syndromes associated with café-au-lait macules (NF2, legius syndrome, McCune Albright syndrome, and multiple familial café-au-lait), conditions associated with pigmented macules (Peutz-Jeghers syndrome, LEOPARD syndrome, neurocutaneous melanosis), and other conditions causing tumor or localized overgrowth (lipomatosis, fibromatoses, speckled lentiginous segmental eruption)^.3

Management

There are no specific guidelines for management of patients with MNF1 as there are for NF1.^1,3 It is important for pediatricians to recognize MNF1 as it is likely underdiagnosed. Patients should be advised of lower risk of complications compared to NF1, but be aware that complications and gonadal involvement are possible.¹ It has thus been recommended that MFN1 patients undergo a complete physical exam and global assessment as well as consider genetic counseling as well.^1–4 Patients with MNF1 can be reassured that, although the involved area can evolve in appearance during childhood, new lesions or spreading of the lesions would not be expected to occur on other areas in adulthood.

Patient Outcome

Our patient is growing and developing normally, has a normal eye exam, and has no signs of systemic NF1.

References

1. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56(11):1433-1443. doi:10.1212/wnl.56.11.1433

2. García-Romero MT, Parkin P, Lara-Corrales I. Mosaic neurofibromatosis type 1: a systematic review. Pediatr Dermatol. 2016;33(1):9-17. doi:10.1111/pde.12673

3. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88. doi:10.1136/jmg.2006.045906

4. Lara-Corrales I, Moazzami M, García-Romero MT, et al. Mosaic neurofibromatosis type 1 in children: a single-institution experience. J Cutan Med Surg. 2017;21(5):379-382. doi:10.1177/1203475417708163