Abstract
Neurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.
Highlights
Neurofibromatosis type 1 (NF1, MIM#162200) is an autosomal dominant inherited genodermatosis and tumour predisposition syndrome with an incidence of 1:3000 (Lammert et al 2005)
NF1 is caused by pathogenic variants in the NF1 gene on chromosome 17q11.2 and characterized by skin pigmentation anomalies such as café-au-lait macules (CALM) and skin-fold freckling, as well as dermal neurofibromas
The diagnostic criteria were revised to facilitate the diagnosis of NF1 in young children who present with isolated CALM but no other disease manifestations or a family history of NF1 and do not meet the strict 1988 clinical diagnostic criteria
Summary
Neurofibromatosis type 1 (NF1, MIM#162200) is an autosomal dominant inherited genodermatosis and tumour predisposition syndrome with an incidence of 1:3000 (Lammert et al 2005). Genetic counselling could be offered to parents and other relatives earlier, and therapeutic interventions for learning disabilities, developmental problems or other complications could be initiated sooner (Cnossen et al 1997) Another problem is that the 1988 clinical diagnostic criteria for NF1 are not specific if children exhibit only CALM and skin-fold freckling. The risk for children with fewer than 6 CALM appears to be significantly lower, as confirmed by other studies (Korf 1992; Nunley et al 2009) These findings indicate that comprehensive genetic testing for pathogenic NF1 variants increases the proportion of children presenting with isolated CALM, who can be diagnosed with NF1, by at least 10–16%. None of 50 children with fewer than 6 CALM who were 29 months or older were given a diagnosis of NF1 on the grounds that they did not have a pathogenic NF1 variant or did not meet the 1988 clinical diagnostic criteria (Ben-Shachar et al 2017). Age of children analysed Total number of children Children with 1 CALM Children with 2 CALM Children with 1 or 2 CALM Children with ≥ 3 CALM
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
