Relationships between severities of dermatological, neurological, and bone manifestations in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease, affects various organs, including the skin, nervous system, and bones.1 The overall severity is graded by combining the severity of each dermatological (D), neurological (N), and bone (B) manifestation, according to the DNB severity grading system in Japan.2 However, there is only limited data available on the current grading system to enable its revision into a better system. Therefore, more data on the current system in real-world settings are required. Clinical manifestations of NF1 are frequently heterogeneous, even among individuals who carry an identical pathogenic variant, such as most familial cases. The grouping of NF1 patients based on clinical manifestations has been attempted, and, indeed, Tabata et al.3 reported correlations between some NF1-related symptoms. Findings on specific correlations may prevent other manifestations being overlooked. Nevertheless, the overall picture of severity in this disease remains unclear. The present study comprehensively investigated the severity of the main NF1-related symptoms using the DNB severity grading system. The ethics committee of The Jikei University School of Medicine approved the study protocol and informed consent was obtained by giving the patients the opportunity to opt-out. The present study was conducted in accordance with the ethical principles of the Declaration of Helsinki. We retrospectively examined the medical records of 621 participants (age range, 1.6– 84.9 years; median age, 32.9 years) including 271 male and 350 female participants. Inclusion criteria were as follows: (i) referral to our hospital between January 2022 and December 2022, (ii) fulfillment of the revised diagnostic criteria by Legius et al.,4 and (iii) the following information available from medical records: age, sex, and symptom severity, graded according to the DNB severity classification system.2 The exclusion criterion was a clinical condition that did not meet the definition of any D-class classification because these individuals could include non-NF1 patients. NF1 patients were examined by our multidisciplinary team that included dermatologists, pediatricians, neurologists, ophthalmologists, neurosurgeons, orthopedic surgeons, and internal medicine physicians. The D-class was recorded as D1 in 268 patients (43.2%), D2 in 93 (15.0%), D3 in 102 (16.4%), and D4 in 158 patients (25.4%). The N-class was recorded as N0 in 407 patients (65.5%), N1 in 194 (31.2%), and N2 in 20 patients (3.2%). The B-class was recorded as B0 in 424 patients (68.3%), B1 in 119 (19.2%), and B2 in 78 (12.6%). Severity stage 1 was observed in 163 patients (26.3%), stage 2 in 166 (26.7%), stage 3 in 32 (5.2%), stage 4 in 53 (8.5%), and stage 5 in 207 patients (33.3%). The distribution is shown in Figure 1a. Correspondence analyses revealed that D1 and D4 were closely associated with N0 and N1 respectively (Figure 1b); D1/D2, D3, and D4 with B0, B1, and B2 respectively; and N0 and N1 with B0 and B1, respectively. Linear regression analyses showed that (i) D-classes correlated with N-classes (correlation coefficient [r] = 0.275, p < 0.001), (ii) D-classes correlated with B-classes (r = 0.285, p < 0.001), and (iii) N-classes correlated with B-classes (r = 0.160, p < 0.001). The analyses also showed that patient ages correlated with D-classes, N-classes, B-classes, and severity stages (r = 0.497, p < 0.001; r = 0.123, p = 0.002; r = 0.161, p < 0.001; and r = 0.398, p < 0.001, respectively) (Supporting Information Figure S1). The present study comprehensively showed correlations between each severity stage in main NF1-related manifestations. The correlations may be at least partially associated with the fact that (i) plexiform neurofibromas sometimes compress cranial nerves and/or peripheral nerve roots at the vertebral column, resulting in neurological problems;5 (ii) plexiform neurofibroma affecting the extremities may concomitantly present with bone manifestations;6 (iii) sphenoid wing dysplasia occasionally results in severe ophthalmological problems through plexiform neurofibroma progression and/or intraorbital meningoencephalocele.7 Correlations were also detected between patient age and severity. Congenital symptoms and age-dependent symptoms may appear in patients with NF1. The latter symptoms may contribute to the relationships because the symptoms commonly emerge with aging. There are a few limitations to this report. The main population examined in this study did not undergo genetic examination. Therefore, the study does not show the relationships of the phenotypes to specific pathogenic mutations. Moreover, the participants who did not meet the definition of any D-class were excluded. Therefore, NF1 patients with minimal neurofibroma, which we could not perceive, may have been excluded. In conclusion, the present study comprehensively showed the close correlations between the severities of the main manifestations in NF1. An attending physician needs to investigate whether symptoms are present in other organs in a patient who presents with any one of severe dermatological, neurological, or bone manifestations. The authors received no extramural financial support. The authors have no conflicts of interest to declare. The ethics committee of The Jikei University School of Medicine, Tokyo, Japan, approved the study protocol, and informed consent was obtained on an opt-out basis. The present study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Data that support the results of this study are available from the corresponding author (Y.N.) upon reasonable request. Figure S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.