NF1 is a multisystem disorder associated with a broad spectrum of complications. Some manifestations are common and seen in the vast majority of affected individuals, whereas others are rare and poorly documented. As an illustration, we will focus on rare tumoral, pulmonary, and skeletal complications associated with NF1.

Background: Neurofibromatosis Type 1 (NF-1) has an increased risk of benign and malignant tumors, as well as short stature, which may be related to growth hormone deficiency (GHD). Current literature on the safety of GHT in this population remains limited. Aim: to evaluate GHT safety in NF-1 patients.
Methods: Retrospective analysis of children with NF-1 followed at our Endocrinology Department, comparing GH-treated (Group A, n=11) and untreated (Group B, n=136) patients, regarding progression of pre-existing lesions (brain tumors/neurofibromas) and development of new lesions.
Results: Of 147 children (53.1% male; mean age 10.3±4.4 years; median follow-up 3.3years), 19(12.9%) had GH deficiency, but only 11 (7.5%) received GHT. Group A was younger at first evaluation (6.9 vs 10.5 years; p=0.007) and had longer follow-up (11 vs 3 years; p<0.001). No significant differences were found between groups regarding optic pathway gliomas (p=0.222), other brain lesions (p=0.693), or neurofibromas (p=0.083). Lesion progression occurred in 37 patients, with similar rates in both groups [3 (27.3%) in Group A vs 34 (25.0%) in Group B; p=1]. In Group A, only brain tumors progressed, whereas 17 (12.5%) patients in Group B experienced neurofibroma progression. New lesions developed in 14 patients (9.5%), all in Group B, predominantly neurofibromas (71.4%). In Group A, progression occurred 5.9±1.5 years after GH initiation; one patient permanently discontinued GH, one temporarily interrupted, and one had already stopped treatment.
Conclusion: GHT was not associated with lesion progression or new lesion development. Nevertheless, treatment decisions should be individualized within a multidisciplinary setting.

Background: This longitudinal study describes the radiological features relating to neurovascular disease in pediatric Neurofibromatosis Type I (NF1) patients at
presentation and on follow-up, correlating the radiological phenotype with both clinical
presentation as well as clinical and radiological outcomes.

Methods: Retrospective cohort study reviewing children referred to the NHS highly specialised commissioned NF1 service at Manchester or London, UK. This represents the UK’s national cohort of children with genetically proven complex NF1 with either clinical concern, or imaging features suggestive of, a prior or acute neurovascular event. Fischer’s exact test was used to determine independence of MRI abnormalities in patients with evidence of ischemic injury, versus no evidence of injury to the brain.

Results: Twenty-four children with clinical or imaging concern for vasculopathy were identified. Twenty-three (96%) had evidence of vasculopathy on MRI with fifteen (65%) having no evidence of chronic infarction on baseline imaging. Two children presented with acute infarcts, one of whom had no evidence of vasculopathy at presentation. There was no statistical link between laterality of disease, location of stenosis or number of vessels involved in regard to infarction risk. There was a statistically significant relationship between grade three stenosis at any site and evidence of ischemic injury to the brain (p=0.026)

Conclusion: The majority of children with NF1 vasculopathy do not have evidence of brain injury at presentation, irrespective of the number of intracranial arteries involved and ancillary MRI findings. The main predictor for ischemic damage to the brain is the degree of absolute stenosis of any one arterial segment.

Aim: To investigate clinical and molecular features of neurofibromatosis type 1 (NF1)-associated breast cancer (BC) in a large multicenter cohort.
Methods: Clinical and histopathological data from 86 NF1 patients with BC (69 with molecular data) were collected, and 111 published cases were reviewed. NF1 variants were assessed in silico, and their distribution across neurofibromin domains was compared with the general NF1 population. Selected variants were functionally characterized in cellular models to assess their effects on neurofibromin activity and RAS-MAPK signaling.
Results: NF1 patients developed BC earlier than the general population (mean 49 years), with missense variant heterozygotes showing the earliest onset (43.9 vs. 49.5 years for truncating variants, p =0.014). Tumors were frequently high-grade (49 %), HER2-enriched (31 %) or luminal B subtypes (31 %), with reduced luminal A (28 %) frequency. NF1+BC patients had more subcutaneous (p =0.006) and plexiform neurofibromas (p <0.00001). Compared with the general NF1 population, they lacked large deletions (0 % vs. 3 %, p =0.0148), showed enrichment for N-HEAT missense variants (70 % vs. 42 %; p =0.0078), and carried recurrent variants significantly enriched in NF1+BC. Structural modeling predicted deleterious effects for >70 % of variants, with proline/arginine substitutions accounting for 83 % of missense variants (vs. 44 % in the general NF1 population, p =0.0012). Functional analysis demonstrated that selected missense variants impair neurofibromin function, resulting in defective RAS downregulation and sustained RAS-MAPK signaling.Conclusions: NF1-associated BC is characterized by earlier onset, aggressive tumor features, and distinct mutational patterns.

Background:
Neurofibromatosis 1 (NF1) is linked to diverse neurological manifestations, but robust, population-based estimates of lifetime neurological morbidity remain limited, with many prior studies being small or clinic-based.
Methods:
In this registry-based cohort study (1977 to 2022), 2,814 individuals with NF1 were identified in the Danish National Patient Registry and RAREDIS and matched 1:10 by sex and birth month and year to 28,088 population comparators. Information on neurological diagnoses, surgeries, and prescribed medications after NF1 diagnosis was obtained from national registries. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Results:
Individuals with NF1 had significantly elevated HRs for a range of disorders, including cerebral palsy (HR 5.5, 95% CI 3.6-8.4), status epilepticus (HR 5.5; 95% CI 3.5-8.5), multiple sclerosis (HR 1.9. 95% CI 1.1-3.3), and dementia (HR 1.7, 95% CI 1.2-2.5). HRs were also increased for surgeries involving central (HR 5.5, 95% CI 4.8-6.2) and peripheral (HR 5.2, 95% CI 4.4-6.3) nervous system. Individuals with NF1 also had higher rates of prescriptions for medication related to neurological conditions, including analgesics (HR 1.4, 95% CI 1.4-1.5), psycholeptics (HR 1.6, 95% CI 1.5-1.7), and cerebrovascular drugs (HR 1.4, 95% CI 1.3-1.5).
Conclusion:
Individuals with NF1 have substantial increased risks of neurological disorders, ranging from early-life conditions to late adult neurodegenerative disease, alongside greater use of neurosurgical care and neuroactive medications. Although age-specific patterns were not directly assessed, findings underscore the need for lifelong awareness of neurological manifestations across all ages in NF1.