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

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.

Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup

“…This is remarkable since the children are often too young at the onset of JMML to display the full spectrum of NF-1-associated symptoms. 5,36 In fact, our genetic data show that the presence of ≥6 café-au-lait macules (or less in the case of affected parents) in a child with JMML is already sufficient to diagnose NF-1 with a very high probability.…”

Cancer Predisposition Syndromes in Neuro-oncology

“…In addition to CALMs, axillary and inguinal freckling also occur in >90% of patients by the age of 7 years. 7 Bone and eye abnormalities such as sphenoid wing dysphasia and Lisch nodules in the eyes also serve as other signs of this condition. 8…”

Neurofibromatosis-1 microdeletiós szindróma.

“…A cutan neurofibromák, melyek sohasem válnak rosszindulatúvá, általában felnőttkorban jelennek meg, és a neurofibromatosis-1-ben szenvedő felnőtt populáció 80-90%-ában fordulnak elő [40]. A microdeletiós betegcsoportra azonban jellemző a cutan neurofibromák nagy száma és korai (pubertás előtti) megjelenése [27,41]. A cutan neurofibromák mellett gyakran subcutan neurofibromák is kialakulhatnak.…”