Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

Hum Genet. 2022 Feb;141(2):177-191. doi: 10.1007/s00439-021-02410-z. Epub 2021 Dec 20.


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.

Publication types

  • Consensus Development Conference, NIH
  • Review

MeSH terms

  • Brain Neoplasms / diagnosis
  • Cafe-au-Lait Spots / diagnosis
  • Child
  • Child, Preschool
  • Colorectal Neoplasms / diagnosis
  • Diagnosis, Differential
  • Female
  • Genes, Neurofibromatosis 1*
  • Genetic Variation
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mosaicism
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neurofibromatosis 1 / diagnosis*
  • Neurofibromatosis 1 / genetics*
  • Neurofibromatosis 1 / pathology

Supplementary concepts

  • Legius syndrome
  • Turcot syndrome