Café au lait spots (CALS) are extraordinarily common; six or more lesions (at least 0.5 cm prior to puberty or 1.5 cm post puberty) are considered one of the criteria for diagnosing neurofibromatosis type I (NF1), and are also seen in a variety of other syndromes. Characteristic CALS in NF1 have a “coast of California” border, while those in McCune-Albright resemble the “coast of Maine”.
As other characteristic features of NF1, notably Lisch nodules, axillary freckles, and neurofibromas, appear subsequent to CALS, dermatologists are often asked to assess the risk for NF1. In order to do this properly, a minimum of a thorough family history, Wood light examination and ophthalmologic evaluation for Lisch nodules and optic gliomas is warranted.
St. John et al detailed eight patients ages 2 to 9 years old with multiple, irregular CALS with feathery borders and no other signs or symptoms of NF-1. Most of these patients had fair complexions with red or blond hair. All patients were evaluated in their pediatric dermatology clinic, three with a geneticist. The number of CALS per patient ranged from 5 to 15 (mean 9.4, median 9). The authors concluded that a subset of children, many with fair complexions and red or blond hair, with an increased number of feathery CAL spots are unlikely to develop NF-1, although genetic testing was not conducted (1).
NF type 6 has been considered an autosomal variant of NF manifested only by multiple CALS. Recent molecular studies have demonstrated that some of these families may display mild variants of NF. The following is the abstract from Pinna et al (2):
Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.
Legius syndrome is a mild NF1 phenotype characterized by multiple CALS with or without freckling and macrocephaly. It is an autosomal dominant disorder due to a mutation in the SPRED1 gene, a feedback regulator of RAS/MAPK signaling. To date, more than 200 cases have been reported (3)
Understandably, parents are anxious when their child is being assessed for NF1. Clearly there are variants that are mild, and perhaps only associated with CALS. St. John et al may have been able to define such a group of children with fair complexions and “feathery” CALS. They concede major limitation of their study was that no genetic testing for either NF1 or SPRED1 was performed on any of their patients. Before any conclusion can be reached if the patients described in this paper represent a benign disorder of pigmentation outside the realm of NF1 (or variant), molecular testing is a must. Fortunately, with increasing sophistication, access, and diminished cost, molecular analysis will be able to predict genotype- phenotype expression and risk prognostication for such patients. Until such time, I agree with the authors that following such patients by the existing guidelines for possible NF or Legius syndrome is appropriate, despite their excellent outlook.
- John J, et al. Multiple café au lait spots in a group of fair skinned children without signs or symptoms of neurofibromatosis type I. Pediatr Dermatol 2016; 5: 526-9.
- Pinna V, et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet 2015; 23: 1068-71.
- Benelli E, et al. Legius syndrome: Case report and review of the literature. Ital J Pediatr 2105; 41: 8.