Impact of neurofibromatosis type 1 in an adult community population

Abstract

Background

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome with varying manifestations and severity. Adult NF1 patients often experience fragmented care, so we sought to characterize the health and demographic features of a community-based population of adults with NF1 and hypothesized that lack of a specialty clinic for adult NF1 patients correlates with unmet needs.

Methods

Retrospective case-control study of all adult cases of NF1 among 4.06 million medical records in a Pacific Northwest population. 122 case charts were reviewed to ascertain NF1 disease features, comorbidities, and severity of disease. A 1:1 control cohort was selected by matching case/control by age, sex, and ZIP code to compare demographic features and health status.

Results

Adult NF1 patients were less likely to have private insurance, be employed, and have children, but were equally likely to be married. One half of cases had disease features compromising health and well-being, and care involved 26 different specialties. Excluding neurofibromas, 43% of cases had cancer compared to 10% of controls [P < .0001, OR 5.38 (2.53–11.4)]. Only 27% of women ages 30–50 had undergone age-appropriate enhanced breast cancer surveillance. Behavioral health problems were found in 60% of NF1 patients compared to 37% of controls [P < .001, OR 2.61 (1.52–4.50)]. 93% of cases referred to a NF1 specialty center underwent a change in management upon establishing care.

Conclusions

NF1 patients may benefit from coordinated management of care in a specialty center.

Neurofibromatosis type 1 (NF1) is an autosomal dominant alteration of the NF1 gene affecting approximately 1 in 3000 individuals worldwide, making it the most common neurocutaneous syndrome and one of the most common tumor predisposition syndromes.¹ Neurofibromin, the protein product of NF1, is a negative regulator of Ras and its dysfunction leads to oncogenic constitutive MAPK activation. Neoplasm is the predominant cause of excess mortality in NF1,² due to peripheral and central nervous system tumors as well as an increased risk of various systemic malignancies. A wide variety of non-neoplastic manifestations are prevalent and greatly impact quality of life, including chronic pain, cosmetic concerns, seizures, neurologic deficits, learning disabilities, and susceptibility to orthopedic and vascular conditions.^3–5 Several additional features of NF1 care exist throughout the lifespan, involving fertility counseling, hypertension screening, and evidence-based enhanced cancer screening.

As a result of a broad range of disease complications, multiple specialty providers are typically involved, with or without an NF1 specialist coordinating care and implementing age-appropriate screening. NF1 specialty care is significantly skewed toward the pediatric population, with the majority of centers run by pediatric-trained providers.⁶ In the United States, there are 63 NF Clinic Network (NFCN) clinics across only 32 states, over half of which are located in children’s hospitals.^7,8 We hypothesized that lack of a specialty clinic for adult NF1 patients corresponds with unmet care needs and sought to characterize the health and demographic features of a relatively unselected, community-based population of adults with NF1, with a goal of promoting access to best practices.

Methods

Cases

IRB approval from an ethical standards committee was received to conduct a retrospective case-control study. Using the search engine SlicerDicer, which is a component of the Epic electronic medical record, we searched the records of 4.06 million patients in the Pacific Northwest and identified 222 individuals who carried NF1 as a diagnosis (Figure 1) between January 1997–November 2020. Among these, 130 patients age ≥ 18 could be confirmed as clinically definite cases of NF1, based on meeting 2 of the 7 NIH Consensus criteria.⁹ A total of 122 cases were analyzed (8 cases could not be matched with a control by age, gender, and zip code). Demographic characteristics that were collected included age, sex, race, ZIP code, insurance, employment, and marital status. In addition to documenting NF1 criteria, several associated disease-related features were evaluated including seizures, cosmetic concerns, pain, weakness, spinal neurofibroma, malignant peripheral nerve sheath tumor (MPNST), glioma, scoliosis, behavioral issues, and other less common manifestations. Most existing NF1 quality of life scales require survey input from patients, thus for simplicity in this retrospective study, severity was qualitatively assigned using the Riccardi scale¹⁰ as defined in Table 1. For each patient, we investigated the number of regional healthcare systems utilized, quantity and type of specialists providing NF1 care, major non-NF1 health issues, hypertension, breast cancer screening, fertility management, whether genetic counseling was documented, and changes to management upon referral to a dedicated NF1 center.

Figure 1.

Flow of cases from identification to inclusion or exclusion.

Table 1.

Definitions and Relative Proportion of Severities Among Cases Using the Riccardi Scale

Severity	Definition	n (%)
1	Some features evident but health and well-being not compromised	22 (16.9)
2	Obvious but not health-compromising features	41 (31.5)
3	Health and well-being compromised but manageable	37 (28.5)
4	Seriously compromised health and well-being in a permanent unmanageable way	30 (23.1)

Controls

A 1:1 control cohort was selected by matching case/control by age, sex and gender, and ZIP code (proxy for socioeconomic factors) in the search engine and selecting the first case on the list provided that person did not have NF1. Control cases were analyzed for selected characteristics, including major medical illness, presence of hypertension, medical insurance, number of healthcare systems involved, number of offspring, employment status, and marital status. A total of 122 controls were analyzed.

Data Availability

Anonymized data not published within this article will be made available by request from any qualified investigator.

Statistics

Student t test was used to test comparisons between groups for normally distributed continuous data, and Mann-Whitney U test for non-normally distributed continuous data. When comparing proportions, χ² test was used except when small sample size necessitated the use of Fisher exact test. Dichotomous outcomes were analyzed using conditional logistic regression in the matched cases-control study design. Displayed P values are double-sided. Stata-12 statistical software (StataCorp LP) was used to analyze data.

Results

Demographic and Socioeconomic Features

Demographic features and health status of adults with NF1 compared to controls are shown in Table 2. Features of note include a higher than expected proportion of women (cases 63% women compared to 53.8% of >4MM population studied), under-representation of nonwhites (cases 81.7% white compared to 51.7% of the population). By comparison with the controls, adult NF1 patients were significantly less likely to have private insurance [P = .004, OR 0.12 (0.03–0.51)], were less likely to be employed [P < .0001, OR 0.27 (0.13–0.55)], and less likely to be married [P < .001, OR 0.24 (0.12–0.49)]. NF1 patients were less likely to have 1 or more offspring, which did not reach statistical significance using logistic regression [0.087, OR 0.60 (0.33–1.08)] but was significant (P < .001) using the Fisher exact test. Medicare was more common in the cases under Medicare age compared to controls.

Table 2.

Demographic and Health Features Comparing NF1 Cases with Age, Gender, and Zip Code Matched Controls

	Cases	Controls	P value , OR (95% CI)
Gender	n (%)	n (%)	1.0
Male	45 (36.9)	45 (36.9)
Female	77 (63.1)	77 (63.1)
Race			.91
White/Caucasian	100 (82.0)	102 (83.6)
Asian	5 (4.1)	5 (4.1)
Hispanic	1 (0.82)	0 (0)
Middle East	2 (1.64)	0 (0)
Black	4 (3.28)	4 (3.28)
Native American	2 (1.64)	2 (1.64)
Unknown/other	8 (6.56)	9 (7.38)
Age			1.0
18–29	18 (14.8)	18 (14.8)
30–39	22 (18.0)	22 (18.0)
40–49	27 (22.1)	27 (22.1
51–59	22 (18.0)	22 (18.0)
60–69	15 (12.3)	15 (12.3)
71–79	13 (10.7)	13 (10.7)
80+	5 (4.1)	5 (4.1)
Insurer			.000
Private	43 (35.3)	83 (68.0)
Medicare/Medicaid	59 (48.4)	37 (30.3)
Tricare	3 (2.5)	0 (0)
Uninsured	17 (13.9)	2 (1.6)
Insurance			.004, OR 0.12 (0.03–0.51)
Yes	105 (86.1)	120 (98.4)
No	17 (13.9)	2 (1.6)
Employment			.000
Employed	58 (47.5)	83 (68.0)
Unemployed	48 (39.3)	37 (30.3)
Unknown	16 (13.1)	2 (1.6)
Employment Satus			.000, OR 0.27 (0.13–0.55)
Employed	58 (47.5)	83 (68.0)
Unemployed/Unknown	64 (52.5)	39 (32.0)
Marriage			.00
Married	50 (41.0)	79 (64.8)
Single	69 (56.6)	43 (35.3)
Unknown	3 (2.5)	0 (0)
Marriage Status			.00, OR 0.24 (0.12–0.49)
Married	50 (41.0)	79 (64.8)
Single/Unknown	72 (59.0)	43 (35.3)
Children			.00
1 or more	41 (33.6)	53 (43.4)
None	47 (38.5)	68 (55.7)
Unknown	34 (27.9)	1 (0.8)
Children Status			.087, OR 0.60 (0.33–1.08)
1 or more	41 (33.6)	53 (43.3)
None/Unknown	81 (66.4)	69 (56.6)
Major Non-NF1 Medical Problem			.019, OR 2.14 (1.14–4.04)
1 or more	86 (71.0)	70 (57.4)
None	36 (29.1)	52 (42.6)
Behavioral Health Problem			.001, OR 2.61 (1.52–4.50)
1 or more	73 (60.0)	44 (36.1)
None	49 (40.2)	78 (63.9)
Diagnosis of Cancer			.000, OR 5.38 (2.53–11.4)
1 or more	47 (38.5)	12 (9.8)
None	75 (61.5)	110 (90.2)

p-values of significance are bolded.

Severity of NF1

Of 130 patients with discernable severity, 51.6% had disease features compromising health and well-being (Riccardi severity ≥ 3). The severity categories with respective relative proportions are summarized in Table 1. 7 patient deaths occurred among NF1 cases during the analyzed time period, though this number did not capture patients who were lost to follow up or moved out of the system. 6 of the 7 deaths captured were attributable to malignancies, including breast cancer (2 cases), GIST (2 cases), GBM (1 case), and pancreatic cancer (1 case). The remaining death was due to cor pulmonale in the setting of COPD.

Healthcare Resources

NF1 patients received care from a median of 4 separate healthcare systems (range 1–10), which was a higher number compared to controls. A median of 2 specialists was involved with each patient for direct NF1-related problems (range 0–6). Across all 130 NF1 patients, a total of 26 different medical specialties were involved in direct NF1-related care, the most frequent of which were neurology/neuro subspecialty other than oncology (n = 42), neuro-oncology (n = 40), neurosurgery (n = 39), medical oncology (n = 17), dermatology (n = 15), plastic surgery (n = 14), genetics (n = 11), pain/palliative care (n = 9), general surgery (n = 9), and orthopedic surgery (n = 8). Thirteen (10%) patients received NF1-related care exclusively from their PCP. About 59.6% (n = 78) of cases had contact with neurology (general or any subspecialty) or genetics. In 32.1% of cases, there was clear documentation that some form of genetic counseling had taken place; this was more likely in those who had been cared for by neuro-oncology or genetics.

Cancer

Excluding benign neurofibromas, 42.7% of NF1 patients (n = 56) experienced a tumor or malignancy of any type compared to 9.8% of controls (n = 12) [P < .0001, OR 5.38 (2.53–11.4)]. Among cases, these included glioma (any grade, n = 20), MPNST (n = 9), breast cancer (n = 9), GIST (n = 8), melanoma (n = 4) pituitary adenoma (n = 4), lung cancer (n = 2), and isolated cases of serous fallopian tube carcinoma, papillary thyroid cancer, colon cancer, pancreatic cancer, ampullary carcinoid, rhabdomyosarcoma, and Waldenstrom macroglobulinemia. 11 (20% of those with cancer) experienced >1 distinct non-neurofibroma neoplasm.

Of 34 females age 30–50, only 8 had undergone age-appropriate enhanced screening for breast cancer outside of the care of an NF1 center and an additional patient had already undergone bilateral mastectomies for breast cancer, leaving 73.5% (25 out of 34) inadequately screened.

Behavioral Conditions

Behavioral health diagnoses of any kind were present in 60.3% (n = 79) compared with 36.6% of controls (n = 45) [P < .001, OR 2.61 (1.52–4.50)]. These included depression (n = 36), anxiety (n = 35), ADHD (n = 11), intellectual impairment (n = 11), insomnia (n = 7), opioid dependence (n = 6), PTSD (n = 4), bipolar disorder (n = 3), autism spectrum disorder (n = 2), schizophrenia (n = 2). Two patients had documented speech impediments/stuttering. Two patients suffered from frequent incarceration and homelessness, and another had frequent admissions for substance overdose. One individual had an admission for suicide attempt with TCA overdose. There was a single diagnosis of gender dysphoria.

Other Disease Features

About 30.5% of NF1 patients had documented hypertension (n = 40). Less common NF1 features among our cases are included in Table 3 and were notable for seizures in 18 (14%), “unidentified bright objects” (UBO) detected in 16 (12%), vasculopathy in 9 (7%), and hydrocephalus/aqueductal stenosis in 8 (6%). Specific vascular problems observed included two cases with carotid stenoses (moyamoya) and one case with basilar stenosis, all complicated by infarcts, two with intracranial aneurysms, two with cryptogenic strokes, one with renal artery stenosis, and one with aortic coarctation.

Table 3.

Summary of Disease Features Among Cohort of NF1 Cases

Feature	n (%)
Pain	83 (63.8)
Behavioral health condition	79 (60.8)
Cosmetic	66 (50.8)
1st degree relative affected	61 (46.9)
Spinal neurofibroma	48 (36.9)
Scoliosis	28 (21.5)
Glioma (any grade)	20 (15.4)
Seizures	18 (13.8)
UBO	16 (12.3)
OPG	12 (9.2)
MPNST	9 (6.9)
Vasculopathy	9 (6.9)
GIST	8 (6.2)
Hydrocephalus/AS	8 (6.2)
Pheochromocytoma	2 (1.5)

UBO, unidentified bright object; OPG, optic pathway glioma; MPNST, malignant peripheral nerve sheath tumor; AS, aqueductal stenosis.

Evaluation in an NF1 Center

Only 21.3% (n = 28) were seen in a dedicated NF1 center. Twenty-six of 28 patients (92.9%) referred to a NF1 center underwent a change in management with regards to screening or treatment. The most frequent changes of management upon establishing care in a NF1 center were acquisition of appropriate imaging (n = 15), initiation of enhanced breast cancer screening (n = 11), initiation of a MEK inhibitor (n = 10), genotyping (n = 8), and hypertension or pheochromocytoma workup (n = 6). To our knowledge, outside of these, no other NF1 patients had been exposed to targeted therapy with MEK inhibition.

Severe Individual Cases

There were several notable individual NF1 complications representative of compromised health and well-being which resulted in a high score on the Riccardi scale. Among them was a 56-year old woman who underwent hysterectomy and cystectomy at age 9 due to a hemorrhagic pelvic mass that was ultimately found to be a neurofibroma, a 53-year old man breathing through a tracheostomy due to a cervical neurofibroma compressing his airway, a 41-year old woman who after neck irradiation for MPNST developed myelodysplastic syndrome that was then complicated by graft versus host disease, a 65-year old woman whose craniofacial neurofibroma resections led to collapse of an external ear canal, leading to recurrent otitis externa and total conductive hearing loss, multiple patients with debilitating weakness as complication of compressive peripheral neuropathies from neurofibromas, and two patients living with a below-the-knee amputation as a result of pseudoarthrosis in childhood.

Discussion

We observed that adult NF1 patients often lack a specialty clinic in which they receive coordinated management of care addressing the broad spectrum and complexity of their disease. Despite 51.6% of identified cases having compromised health and well-being due to NF1, only 21.3% were receiving care from a dedicated adult NF clinic. We also observed a multiplicity of specialty providers and healthcare systems involved, which is not unique to our population under study but is likely a compounding factor in this widely variable disease requiring conscientious anticipatory guidance, monitoring, and treatment. Prior studies have shown that a majority of adults with NF1 have no regular health monitoring after transitioning from the pediatric service due to varying factors that include lack of awareness of monitoring guidelines, lack of knowledge of where or how to access health monitoring, and beliefs that nothing can be done for NF1.¹¹ A quality improvement study evaluating access to cancer genetics services has implicated inconsistent referral for services related to lack of knowledge dissemination among medical providers.¹² Within our population, these deficiencies measurably manifested with only a small minority receiving fertility counseling and age-appropriate breast cancer surveillance, as well as implied unmet care needs in cosmetic, pain, and behavioral health domains. We observed that upon establishing care in a dedicated center, 26 of 28 adult patients underwent a substantial change in management tailored to their needs.

A limitation of our study is the known potential inaccuracies inherent to manual chart review.¹³ In order for a case to be included in our study, patients had to have been assigned Neurofibromatosis Type 1 on their EMR problem list, and then upon our review had to clearly meet clinical criteria. The heterogeneous documentation and billing among providers made this difficult as demonstrated by our exclusion of 41% of such patients and interestingly brought to attention an element of knowledge deficiency of clinical criteria among many frontline providers seeing potential NF1 patients. This likely skewed our severity scale analysis toward more severe phenotypes and might not have captured those in the population with undocumented cutaneous manifestations. Our study also only accounted for patients who had had contact with our medical system and would have missed those exclusively receiving care at other regional centers. The expected prevalence of NF1 in our total population should have been 1200–1500, from which pediatric patients were excluded and milder phenotypes were likely missed. Given that NF1 is not known to have a sex or race predominance, the different proportions observed among cases compared to that expected from the overall population imply additional factors impacting utilization and access to care. Finally, our dataset did not capture other potential confounders of health outcomes such as smoking or alcohol use. Nevertheless, our study captured a large proportion of the Pacific Northwest, including rural populations from Idaho and Montana, and within these confines likely generalizes well to a broader population of obviously affected NF1 patients.

Our data suggest a role for establishing and increasing access to dedicated adult NF1 centers to optimize surveillance and management. In areas where this is not available, care is likely best integrated under the purview of adult general neurologists, neuro-oncologists, or geneticists experienced in managing the disease. Patient registries may provide an opportunity to optimize care by streamlining patient access to NF Centers and identifying disparities through the collection of demographic and outcome data. In particular, the Children’s Tumor Foundation’s NF registry currently reports over 10 000 active participants,¹⁴ and would benefit from further recruitment to better generalize to the larger population of NF1 patients. Further research should include large scale analysis of trends among youth and adults that might inform advocacy and policy at the national level as well as the development of evidence-based guidelines for management, such as the robust guidelines available from the Cystic Fibrosis Foundation.¹⁵

Guidelines for NF1 care are derived from expert opinion, and an excellent guide exists (Stewart DR, Genetics in Medicine 2018 20:671-82). Our experience has shown that important issues to consider in a specialty clinic include a standardized screening tool for morbidities seen in adult NF1 patients, family history and reproductive counseling, genetic testing, evaluation of the causes of hypertension, prompt investigation of progressive pain, increasing lesion size or neurological deficit, enhanced breast cancer screening in women ages 30 to 50, attention to morbidity from cutaneous neurofibromas, and pain management.

In conclusion, a systematic approach to adult NF1 care is warranted either in dedicated NF1 centers or under the supervision of a qualified general neurologist. This may require more deliberate knowledge dissemination of disease criteria and complications among frontline providers to improve surveillance and quality of life optimization.

Funding

None.

Conflict of interest statement. The authors have no conflicts of interest to declare. No writing assistance was utilized in the production of this manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of Defense, nor the US Government.

Authorship statement. T.A.G. primary author, study design, data acquisition. P.B.M. data acquisition, editing. G.D.P. statistical analysis, editing. J.W.H. concept, study design, editing.