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. 2025 Jun 25;105:43416. doi: 10.2340/actadv.v105.43416

Hospital Use, Morbidity, and Cancer Risk by Age Group in Neurofibromatosis Type 1: A Nationwide Retrospective Cohort Study

Minsu KIM 1, Suhyun HAN 2, Chong Won CHOI 1, Bo Ri KIM 1,✉, Sang Woong YOUN 1
PMCID: PMC12228043  PMID: 40557967

Abstract

Neurofibromatosis type 1 (NF1) affects multiple organs progressively, leading to a shortened life expectancy. This study aimed to identify the complications that are prominent in each age group by comparing 28,082 patients with NF1 and 84,246 matched controls. Benign and malignant neoplasms along with neurological complications were the primary contributors to hospital use across most age groups. Respiratory and circulatory disorders were a common cause of hospital use in children and older adults, respectively. Except for soft tissue and central nervous system-originated malignancies, which are well-established NF1-related tumours, the highest rate ratios (RR) of malignancies with statistical significance was observed in the adrenal gland (0–9 years, RR 50.67, 95% CI 6.74–380.76); female genital organs (10–14 years, RR 12.06, 95% CI 1.35–107.93); respiratory and intrathoracic organs (15–19 years, RR 15.10, 95% CI 1.76–129.22; 20–29 years, RR 7.59, 95% CI 2.94–19.56; ≥ 60 years, RR 1.38, 95% CI 1.18–1.61); lip, oral cavity, and pharynx (30–39 years, RR 6.11, 95% CI 1.53–24.42); and bone and articular cartilage (40–49 years, RR 3.06, 95% CI 1.37–6.81; 50–59 years, RR 4.73, 95% CI 2.35–9.50). Comorbidities and malignancies that predominantly affect patients vary by age group; physicians should be aware of the appropriate management strategies throughout their lifespan.

Key words: neurofibromatosis 1, genetic skin disease, comorbidity, cancer, epidemiology

SIGNIFICANCE

Neurofibromatosis type 1 invades various organs simultaneously and is accompanied by diverse comorbidities and malignancies. We identified which system imposes the greatest health-related burden on patients with neurofibromatosis type 1 in each age group. Malignant and benign tumours as well as neurological complications posed significant burdens throughout the lifespan of patients with neurofibromatosis type 1. However, the primary reasons for hospital use and the types of malignancies that occurred varied by age group. Comorbidities commonly observed at each stage of life must be thoroughly understood to provide comprehensive treatment for patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a genetic disorder accompanying various clinical manifestations, including numerous benign and malignant neoplasms (1). They result in a reduction in life expectancy of approximately 8–20 years compared with the general population (2, 3).

Because of the multisystemic nature of the disease, patients with NF1 frequently require multidisciplinary treatment, which places a considerable burden on both patients and physicians (4, 5). Therefore, a comprehensive understanding of comorbidities across the lifespan of these patients, as well as their impact on the national healthcare system, is essential for adequate treatment. However, most studies examining comorbidities in patients with NF1 have focused on mortality data, emphasizing complications that contribute to death (2, 3, 6–9). Although several epidemiological studies have investigated comorbidities throughout the lifespan of patients with NF1, these analyses have primarily been limited to hospitalized patients’ records (10, 11).

Korea has a national health insurance system that provides coverage for most patients. Additionally, rare disorders, including NF1, are designated as conditions requiring specialized management, ensuring that patients can access hospitals without financial barriers. Along with these, Korea’s high accessibility to medical care is expected to facilitate more comprehensive and detailed patient research.

We aimed to analyse the outpatient and inpatient medical history of patients diagnosed with NF1 to identify all comorbidities, including relatively mild conditions, and to determine whether major changes in disease patterns occur with age. Understanding which organ systems are primarily affected at each stage of life may aid in the efficient management of NF1 and development of treatment guidelines.

MATERIALS AND METHODS

Study design and data source

A population-based retrospective cohort study was conducted using the Health Insurance Review and Assessment (HIRA) database between 1 January 2009, and 31 December 2023 (HIRA research data: M20240820001). As more than 98% of Koreans are covered by a single national healthcare system, the HIRA dataset provides overall medical information on each patient by anonymously reviewing them using personal registration codes.

Study population

Korea has a registration programme to aid financially patients with rare and intractable diseases, including NF1. After confirmation by specialists that patients meet the clinical diagnostic criteria and have undergone adequate radiological evaluation, those diagnosed with NF1 are assigned a V156 diagnostic code, which is highly reliable.

The NF1 group included patients whose medical records contained the V156 code or the International Classification of Diseases, 10th revision (ICD-10) code for neurofibromatosis (Q85.0). Patients with any other phacomatoses, not elsewhere classified (Q85) diagnostic codes (tuberous sclerosis [Q85.1], other phacomatoses, not elsewhere classified [Q85.8], phacomatosis, unspecified [Q85.9]) were excluded. As NF1 and neurofibromatosis type 2 cannot be distinguished based on ICD-10 codes, as with a previous study, patients with records of diagnostic codes for benign neoplasm of meninges (D32) or benign neoplasm of cranial nerves (D33.3), which indicate a diagnosis of neurofibromatosis type 2, were additionally excluded (11).

Because extracting data from the general population was not possible, the control group was defined as patients with diagnostic codes for haemangioma (D18.0). In the Korean system, since 2011, it has been possible to distinguish patients with haemangiomas of the skin and soft tissue from those with haemangiomas of other origins. Therefore, they were selected as the control group because they are associated with fewer systemic complications and comorbidities (12). Patients whose records contained the ICD-10 code Q85.0 were excluded. Each patient with NF1 was matched to 3 controls according to sex and birth year.

Evaluation of hospital use patterns and comorbidities

Every hospital visit was examined irrespective of the date of NF1 diagnosis because NF1 is a congenital disorder. To make the control group representative of the general population, hospital visits associated with the primary diagnosis of haemangioma were excluded.

Hospital use patterns were classified according to the main diagnostic group for the primary diagnosis at each visit. Absolute excess risk (AER) was calculated for hospital use in each diagnostic group by subtraction; that is, we analysed how many more times patients with NF1 used outpatient or inpatient hospital care for each diagnostic group per 10,000 person-years.

The incidence rate was calculated to analyse comorbidities. Incidence was defined as at least 1 hospitalization or 3 outpatient visits for any primary or all secondary diagnoses. Detailed diagnostic codes of the comorbidities used for analysis are provided in Table SI.

Statistical analysis

Continuous and categorical variables were compared using Student’s t-test, Pearson’s χ2 test or Fisher’s exact test, as appropriate.

For overall cancer cases, the standardized incidence ratio (SIR) was calculated at 1-year age intervals by sex. The trend line was determined using locally estimated scatterplot smoothing method.

Statistical analyses were performed using R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Clinical characteristics

Altogether, 28,082 patients with NF1 were matched to 84,246 patients in the control group (Table I, Fig. 1). Among patients with NF1, 18.5% were diagnosed with any type of cancer at least once during the observation period, which was significantly higher than that of the control group (12.9%, p < 0.001). Age at first diagnosis of any cancer was also low in the NF1 group (50.22 ± 19.25 years vs 56.92 ± 15.74 years, p < 0.001).

Table I.

Demographics of the neurofibromatosis type 1 group and control group

Demographics NF1 Control p-value
Total, n (%) 28,082 84,246
 Male 13,679 (48.7) 41,037 (48.7)
 Female 14,403 (51.3) 43,209 (51.3)
Birth year, n (%)
 1920–1939 871 (3.1) 2,613 (3.1)
 1940–1959 5,675 (20.2) 17,025 (20.2)
 1960–1979 8,629 (30.7) 25,887 (30.7)
 1980–1999 7,195 (25.6) 21,585 (25.6)
 2000–2019 5,227 (18.6) 15,681 (18.6)
 2020–2023 485 (1.7) 1,455 (1.7)
Hospital use, mean ± SD
  Number of outpatient clinic visit 248.31 ± 242.96 246.92 ± 239.94 0.40
 Number of hospitalizations 6.26 ± 19.59 5.44 ± 29.57 < 0.001
  Length of hospitalizations per admission (days) 6.24 ± 5.28 5.22 ± 4.37 < 0.001
  Total length of hospitaliza-tions per patient (days) 59.85 ± 256.84 39.28 ± 209.41 < 0.001
Cancer diagnosis, n (%) 5,182 (18.5) 10,826 (12.9) < 0.001
  Age at first cancer diagnosis (years) 50.22 ± 19.25 56.92 ± 15.74 < 0.001
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SD: standard deviation; NF1: neurofibromatosis type 1.

Fig. 1.

Fig. 1

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Flowchart of study population selection. ICD-10: International Classification of Diseases, 10th revision

Hospital use

Compared with those of controls, patients with NF1 showed a significantly higher number of admissions (6.26 ± 19.59 vs 5.44 ± 29.57, p < 0.001), length of each hospitalization (6.24 ± 5.28 days vs 5.22 ± 4.37 days, p < 0.001), and total length of hospitalization (59.85 ± 256.84 days vs 39.28 ± 209.41 days, p < 0.001). The number of outpatient clinic visits was also high, but it failed to reach statistical significance (248.31 ± 242.96 vs 246.92 ± 239.94, p = 0.40).

Specifically, regarding outpatient clinic visits and inpatient hospitalizations, treatments related to neoplasms, the nervous system, and mental and behavioural disorders showed high AER (Table SII). Hospitalizations related to mental and behavioural disorders had the longest hospitalization days per admission (15.18 ± 10.79 days) and total hospitalization days (335.17 ± 784.88 days).

Analysing which diagnostic groups-related hospital use was more prominent by age group, a high AER was confirmed in neoplasms and nervous system disorders in both outpatient and inpatient settings across most age groups (Fig. 2, Table SIII). Additionally, the AER of hospital use was high owing to problems related to the respiratory system in the younger age group and circulatory system in the older age group. Hospital use because of mental and behavioural disorders was prominent in both pre-adulthood and old age.

Fig. 2.

Fig. 2

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Incidence rate for each main diagnostic group according to age group in the neurofibromatosis type 1 (NF1) group and control (C) group for (A) outpatient clinic visits and (B) inpatient hospitalizations.

Morbidities

In patients with NF1, we noticed especially high rate ratios (RR) for other congenital malformations of the central nervous system (CNS; RR 14.71, 95% CI 5.61–38.54), Arnold Chiari malformation (RR 7.66, 95% CI 3.37–17.39), mental retardation (RR 5.73, 95% CI 4.91–6.68), and hydrocephaly (RR 4.76, 95% CI 3.95–5.74), which are well-known complications associated with NF1 (Table II) (11).

Table II.

Incidence of non-neoplastic comorbidities and complications that showed a high rate ratio in patients with neurofibromatosis type 1 compared with that in the control group

Conditions NF1 Control RR (95% CI)
Infectious and parasitic disease
 Tuberculosis 474 1,080 1.35 (1.21, 1.50)
 Other bacterial diseases 1,797 5,219 1.05 (1.00, 1.11)
 Sepsis 737 1,405 1.61 (1.47, 1.76)
Diseases of the blood and blood-forming organs
 Anaemia 7,381 18,437 1.26 (1.23, 1.29)
 Coagulation defects, purpura 1,183 2,987 1.21 (1.14, 1.30)
Endocrine, nutritional, and metabolic diseases
 Hypoparathyroidism 156 394 1.21 (1.01, 1.46)
  Hyperfunction of pituitary gland 229 554 1.27 (1.09, 1.48)
 Hypofunction of pituitary gland 113 175 1.98 (1.56, 2.51)
  Lack of expected normal physiological development in childhood and adults 598 741 2.49 (2.23, 2.77)
 Malnutrition 4,991 13,843 1.11 (1.07, 1.15)
Mental and behavioural disorders
 Dementia 2,652 6,646 1.23 (1.18, 1.29)
  Mental and behavioural disorders due to psychoactive substance use 416 1,115 1.14 (1.02, 1.28)
 Schizophrenia 403 891 1.39 (1.23, 1.56)
 Mood disorder 5,960 15,844 1.17 (1.13, 1.20)
 Depressive disorder 5,326 14,219 1.16 (1.12, 1.20)
 Bipolar disorder 1,258 3,025 1.28 (1.20, 1.36)
 Anxiety disorder 6,736 19,461 1.06 (1.03, 1.09)
 Sleep disorder 6,223 17,188 1.12 (1.09, 1.15)
  Mental retardation 464 250 5.73 (4.91, 6.68)
  Psychological development disorder 323 329 3.02 (2.59, 3.52)
  Attention-deficit hyperactivity disorder 742 1,113 2.06 (1.87, 2.26)
Diseases of the nervous system
  Encephalitis, myelitis, and encephalomyelitis 58 101 1.76 (1.27, 2.43)
  Parkinson’s disease and Parkinsonism 498 1,228 1.24 (1.12, 1.38)
 Multiple sclerosis 35 42 2.55 (1.63, 4.00)
 Epilepsy 2,000 3,300 1.89 (1.78, 1.99)
 Headache 11,150 32,823 1.05 (1.03, 1.07)
 Hydrocephaly 279 180 4.76 (3.95, 5.74)
 Spinal cord compression 86 172 1.53 (1.18, 1.98)
  Other disorders of central nervous system 36 49 2.25 (1.46, 3.46)
 Arnold Chiari malformation 20 8 7.66 (3.37, 17.39)
  Other congenital malformations of the central nervous system 24 5 14.71 (5.61, 38.54)
Diseases of the eye and adnexa
  Retinal detachments and breaks 428 1,003 1.31 (1.17, 1.47)
 Optic neuritis 131 123 3.27 (2.55, 4.18)
 Disorder of optic nerve 546 937 1.79 (1.61, 1.99)
 Strabismus 1,622 2,587 1.95 (1.84, 2.08)
  Disorders of refraction and accommodation 12,355 37,404 1.02 (1.00, 1.04)
 Myopia 4,699 13,696 1.06 (1.02, 1.10)
 Visual disturbances 1,429 2,385 1.86 (1.74, 1.98)
  Visual impairment including blindness 133 201 2.03 (1.63, 2.53)
Diseases of the circulatory system
 Primary hypertension 8,223 24,250 1.03 (1.01, 1.06)
 Renovascular hypertension 38 42 2.77 (1.79, 4.30)
 Ischaemic heart disease 3,085 9,071 1.04 (1.00, 1.08)
  Pulmonary arterial hypertension 36 73 1.51 (1.01, 2.25)
 Pericarditis 90 197 1.40 (1.09, 1.80)
 Arrhythmia 3,358 9,732 1.06 (1.02, 1.10)
 Heart failure 1,671 4,362 1.18 (1.11, 1.24)
 Cardiopathy 374 1,014 1.13 (1.00, 1.27)
 Haemorrhagic stroke 416 786 1.62 (1.44, 1.83)
 Ischaemic stroke 1,401 3,333 1.29 (1.21, 1.38)
Diseases of arteries, arterioles, and capillaries
 Aneurysm and dissection 200 387 1.58 (1.34, 1.88)
Diseases of the respiratory system
 Pneumonia 6,542 17,776 1.14 (1.11, 1.17)
 Emphysema 542 728 2.29 (2.05, 2.56)
 Asthma 11,450 33,206 1.07 (1.05, 1.09)
  Adult respiratory distress syndrome 41 53 2.37 (1.58, 3.56)
 Pulmonary oedema 148 328 1.38 (1.14, 1.68)
 Pneumothorax 230 441 1.60 (1.36, 1.88)
 Respiratory failure 531 1,059 1.54 (1.39, 1.71)
Diseases of the digestive system
 Peptic ulcer 12,429 37,016 1.03 (1.00, 1.05)
  Polyp of stomach and duodenum 428 1,127 1.16 (1.04, 1.30)
  Paralytic ileus and intestinal obstruction without hernia 811 1,862 1.34 (1.23, 1.45)
 Constipation 8,902 23,768 1.17 (1.14, 1.20)
 Functional diarrhoea 3,388 9,842 1.06 (1.02, 1.10)
Diseases of anal and rectal regions
  Haemorrhoids and perianal venous thrombosis 3,509 10,135 1.06 (1.02, 1.10)
 Peritonitis 228 481 1.45 (1.24, 1.70)
Diseases of liver
 Toxic liver disease 1,143 3,028 1.16 (1.08, 1.24)
Disorders of gallbladder, biliary tract and pancreas
 Acute pancreatitis 702 1,839 1.17 (1.07, 1.28)
 Gastrointestinal haemorrhage 852 1,984 1.32 (1.22, 1.43)
Diseases of the musculoskeletal system and connective tissue
 Dorsopathies 19,284 57,370 1.03 (1.01, 1.05)
 Scoliosis 1,270 1,977 2.00 (1.86, 2.14)
 Osteopathies and chondropathies 6,173 16,445 1.16 (1.13, 1.20)
 Osteoporosis 4,306 10,978 1.21 (1.17, 1.26)
 Disorders of continuity of bone 244 312 2.40 (2.03, 2.84)
 Bone deformity 90 196 1.41 (1.10, 1.81)
Diseases of the genitourinary system
 Renal tubule-interstitial diseases 1,572 4,537 1.06 (1.00, 1.13)
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NF1: neurofibromatosis type 1, RR: rate ratio, 95% CI: 95% confidence interval.

Comorbidities with an RR over 2.0 included optic neuritis (RR 3.27, 95% CI 2.55–4.18), psychological development disorder (RR 3.02, 95% CI 2.59–3.52), renovascular hypertension (RR 2.77, 95% CI 1.79–4.30), multiple sclerosis (RR 2.55, 95% CI 1.63–4.00), lack of expected normal physiological development (RR 2.49, 95% CI 2.23–2.77), disorders of continuity of bone (RR 2.40, 95% CI 2.03–2.84), adult respiratory distress syndrome (RR 2.37, 95% CI 1.58–3.56), emphysema (RR 2.29, 95% CI 2.05–2.56), other disorders of CNS (RR 2.25, 95% CI 1.46–3.46), attention-deficit hyperactivity disorder (RR 2.06, 95% CI 1.87–2.26), visual impairment including blindness (RR 2.03, 95% CI 1.63–2.53), and scoliosis (RR 2.00, 95% CI 1.86–2.14).

Some disorders, including type 2 diabetes mellitus (RR 0.92, 95% CI 0.89–0.95), viral hepatitis (RR 0.87, 95% CI 0.82–0.92), alcoholic liver disease (RR 0.84, 95% CI 0.78–0.91), and obesity (RR 0.66, 95% CI 0.53–0.82), were observed at low rates in patients with NF1 (Table SIV).

Cancer risk

Patients with NF1 showed the highest RRs for malignancies of the spinal cord (RR 199.28, 95% CI 27.65–1436.09) and cranial nerves (RR 88.95, 95% CI 32.83–241.00), primarily driven by a significant increase in optic nerve tumours. Elevated risks were also observed for malignancies of the small intestine (RR 26.90, 95% CI 18.32–39.51), brain (RR 8.47, 95% CI 6.82–10.53), meninges (RR 7.88, 95% CI 3.29–18.86), and mesothelial and soft tissue (RR 6.87, 95% CI 6.01–7.86), which includes malignant peripheral nerve sheath tumours (Table III). Hepatocellular carcinoma (HCC; RR 0.78, 95% CI 0.64–0.94) and non-melanoma skin cancer (NMSC; RR 0.82, 95% CI 0.69–0.98) were less frequently observed in patients with NF1. However, NMSC was detected at a significantly younger age in patients with NF1 (61.99 ± 17.46 years vs 66.91 ± 16.85 years, p = 0.002).

Table III.

Incidence of neoplasms in patients with neurofibromatosis type 1 and the control group

Neoplasms Number Age of first diagnosis
NF1 Control RR (95% CI) NF1 Control p-value
Malignant
 Lip, oral cavity, and pharynx 53 114 1.42 (1.03, 1.97) 55.11 ± 19.58 60.86 ± 13.15 0.056
 Digestive organs 1,252 2,691 1.43 (1.34, 1.53) 58.83 ± 13.56 62.19 ± 12.88 < 0.001
 Oesophagus 19 45 1.29 (0.76, 2.21) 63.00 ± 12.20 66.96 ± 10.10 0.223
 Stomach 302 803 1.15 (1.01, 1.31) 61.06 ± 13.29 62.98 ± 11.79 0.028
 Small intestine 254 29 26.90 (18.32, 39.51) 52.96 ± 12.23 65.79 ± 10.50 < 0.001
 Colorectum 821 1,574 1.60 (1.47, 1.74) 58.32 ± 14.05 63.19 ± 12.15 < 0.001
 Anus and anal canal 10 17 1.80 (0.82, 3.93) 63.00 ± 12.55 61.59 ± 11.05 0.772
 Liver and intrahepatic bile ducts 231 718 0.99 (0.85, 1.14) 58.90 ± 13.74 61.00 ± 13.77 0.044
 Hepatocellular carcinoma 131 515 0.78 (0.64, 0.94) 58.66 ± 13.58 60.89 ± 13.01 0.092
 Gallbladder 24 47 1.56 (0.96, 2.56) 64.75 ± 10.51 70.60 ± 10.39 0.031
 Other and unspecified parts of biliary tract 100 100 3.06 (2.32, 4.04) 61.51 ± 13.34 65.87 ± 12.33 0.017
 Pancreas 142 295 1.48 (1.21, 1.80) 61.42 ± 14.49 63.75 ± 13.99 0.112
 Respiratory and intrathoracic organs 388 719 1.65 (1.46, 1.87) 59.45 ± 15.82 66.07 ± 12.46 < 0.001
 Bronchus and lung 335 613 1.67 (1.47, 1.91) 61.62 ± 13.63 67.38 ± 11.50 < 0.001
 Bone and articular cartilage 69 74 2.86 (2.06, 3.97) 39.75 ± 20.13 46.46 ± 21.70 0.057
 Melanoma 42 86 1.50 (1.03, 2.16) 61.21 ± 11.99 60.71 ± 17.94 0.851
 Non-melanoma skin cancer 155 577 0.82 (0.69, 0.98) 61.99 ± 17.46 66.91 ± 16.85 0.002
 Mesothelial and soft tissue 693 311 6.87 (6.01, 7.86) 42.00 ± 18.78 55.70 ± 23.17 < 0.001
 Mesothelioma 5 6 2.55 (0.78, 8.36) 42.60 ± 15.73 64.83 ± 19.72 0.067
 Peripheral nerves and autonomic nervous system 448 9 153.24 (79.21, 296.44) 41.21 ± 17.75 63.67 ± 10.74 < 0.001
 Breast 466 861 1.66 (1.48, 1.86) 49.57 ± 10.61 52.34 ± 11.17 < 0.001
 Female genital organs 173 415 1.28 (1.07, 1.52) 50.90 ± 14.80 52.13 ± 14.74 0.358
 Cervix uteri 43 131 1.01 (0.71, 1.42) 54.51 ± 12.03 52.80 ± 13.91 0.439
 Corpus uteri 50 125 1.23 (0.88, 1.70) 50.82 ± 8.61 52.53 ± 11.87 0.293
 Ovary 64 147 1.33 (0.99, 1.79) 47.12 ± 16.61 51.95 ± 16.06 0.052
 Male genital organs 316 863 1.12 (0.99, 1.28) 67.48 ± 11.07 67.26 ± 10.40 0.766
 Prostate 305 833 1.12 (0.98, 1.28) 68.64 ± 9.32 68.05 ± 9.00 0.342
 Testis 10 18 1.70 (0.79, 3.69) 35.00 ± 8.64 37.72 ± 17.39 0.585
 Urinary tracts 153 492 0.95 (0.79, 1.14) 60.82 ± 15.07 63.16 ± 14.23 0.09
 Kidney, except renal pelvis 66 227 0.89 (0.68, 1.17) 59.17 ± 13.66 59.12 ± 14.73 0.982
 Renal pelvis 8 29 0.84 (0.39, 1.85) 71.88 ± 9.39 68.24 ± 15.96 0.424
 Bladder 81 236 1.05 (0.82, 1.35) 62.02 ± 14.99 66.67 ± 12.62 0.014
 Eye, brain, and other parts of the CNS 488 139 10.82 (8.96, 13.06) 30.14 ± 21.69 54.85 ± 21.02 < 0.001
 Eye and adnexa 10 15 2.04 (0.92, 4.55) 35.60 ± 31.86 52.27 ± 21.90 0.17
 Meninges 18 7 7.88 (3.29, 18.86) 41.67 ± 21.26 55.29 ± 17.45 0.123
 Brain 306 111 8.47 (6.82, 10.53) 32.35 ± 19.49 55.22 ± 21.75 < 0.001
 Spinal cord 65 1 199.28 (27.65, 1436.09) 37.65 ± 21.18 37.00 –
 Cranial nerves 116 4 88.95 (32.83, 241.00) 12.09 ± 14.46 51.00 ± 12.62 0.007
 Optic nerve 103 0 – 8.08 ± 7.51 – –
 Other cranial nerves 13 4 9.96 (3.25, 30.53) 43.92 ± 16.97 51.00 ± 12.62 0.40
 Thyroid and other endocrine glands 571 1,591 1.10 (1.00, 1.21) 48.31 ± 14.69 49.38 ± 13.17 0.126
 Thyroid gland 472 1,565 0.92 (0.83, 1.02) 50.20 ± 12.23 49.37 ± 12.97 0.203
 Ill-defined, other secondary and unspecified sites 994 1,345 2.27 (2.09, 2.47) 51.97 ± 18.29 59.81 ± 16.51 < 0.001
 Lymphoid, hematopoietic and related tissue 199 428 1.43 (1.20, 1.69) 46.03 ± 25.03 54.50 ± 19.33 < 0.001
 Hodgkin lymphoma 6 7 2.63 (0.88, 7.81) 52.83 ± 23.28 61.00 ± 13.19 0.47
 Non-Hodgkin lymphoma 73 209 1.07 (0.82, 1.40) 52.47 ± 20.19 56.20 ± 17.22 0.161
 Multiple myeloma 31 49 1.94 (1.24, 3.04) 64.10 ± 12.70 65.29 ± 10.31 0.663
 Leukaemia 63 124 1.56 (1.15, 2.11) 32.43 ± 26.19 50.02 ± 22.90 < 0.001
 Multiple independent sites 8 8 3.06 (1.15, 8.16) 60.75 ± 11.02 70.38 ± 5.26 0.05
Benign
 In situ neoplasms 367 1,030 1.09 (0.97, 1.23) 54.35 ± 13.85 55.83 ± 16.13 0.094
 Benign neoplasms
 Mouth, pharynx, and major salivary glands 268 812 1.01 (0.88, 1.16) 42.78 ± 21.73 47.48 ± 19.65 0.002
  Colon, rectum, anus, anal canal, other and ill-defined parts of digestive system 2,280 6,743 1.04 (0.99, 1.09) 56.36 ± 12.12 57.94 ± 11.71 < 0.001
  Middle ear, respiratory system, other and unspecified intrathoracic organs 393 577 2.09 (1.84, 2.38) 45.61 ± 19.64 57.29 ± 15.03 < 0.001
 Bone and articular cartilage 283 470 1.85 (1.60, 2.14) 36.78 ± 20.92 37.16 ± 20.41 0.808
 Breast 890 3,216 0.84 (0.78, 0.91) 43.90 ± 12.07 44.00 ± 11.77 0.832
  Leiomyoma of uterus, other benign neoplasms of uterus, ovary, other and unspecified female genital organs 2,123 6,613 0.98 (0.94, 1.03) 43.12 ± 10.91 43.27 ± 10.88 0.586
 Male genital organs 87 328 0.81 (0.64, 1.03) 51.89 ± 18.47 50.38 ± 18.36 0.499
 Urinary organs 127 426 0.91 (0.75, 1.11) 55.87 ± 16.18 60.18 ± 13.63 0.007
 Eye and adnexa 182 275 2.03 (1.68, 2.45) 35.60 ± 20.25 48.04 ± 22.18 < 0.001
 Brain and other parts of CNS 633 219 8.95 (7.68, 10.44) 38.33 ± 18.95 52.95 ± 17.55 < 0.001
  Thyroid gland, other and unspecified endocrine glands 1,129 2,958 1.17 (1.09, 1.26) 49.25 ± 14.34 51.41 ± 13.48 < 0.001
 Neoplasms of unspecified behaviour 1,493 1,761 2.64 (2.46, 2.83) 43.92 ± 19.68 52.73 ± 18.85 < 0.001
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NF1: neurofibromatosis type 1, RR: rate ratio, 95% CI: 95% confidence interval, CNS: central nervous system.

As shown in Fig. 3, the SIR of total malignancies was high in the younger age groups. In particular, compared with controls, the risk of malignancies of mesothelial and soft tissue, and eye, brain, and other parts of the CNS was high in all age groups of patients with NF1 (Table SV). Aside from these, the highest RR with statistical significance was observed in malignancies of the thyroid and other endocrine glands in the 0–9 years group (RR 16.89, 95% CI 4.95–57.64), in which incidence was detected solely from the adrenal gland (incidence rate 4.55/10,000 person-years, RR 50.67, 95% CI 6.74–380.76). For the 10–14 years group, the highest RR was observed in malignancies of the female genital organs (RR 12.06, 95% CI 1.35–107.93), with the highest incidence rate in the ovary (1.42/10,000 person-years), followed by the vulva and vagina (0.47/10,000 person-years). The highest RR was observed in malignancies of the respiratory and intrathoracic organs in the 15–19 years group (RR 15.10, 95% CI 1.76–129.22) and 20–29 years group (RR 7.59, 95% CI 2.94–19.56). Specifically, in the 15–19 years group, the highest incidence rate was observed in the heart, mediastinum, and pleura (1.75/10,000 person-years), whereas in the 20–29 years group, it was observed in the bronchus and lung (1.76/10,000 person-years). Additionally, the highest RR was detected in malignancies of the lip, oral cavity, and pharynx (30–39 years, RR 6.11, 95% CI 1.53–24.42); bone and articular cartilage (40–49 years, RR 3.06, 95% CI 1.37–6.81; 50–59 years, RR 4.73, 95% CI 2.35–9.50); and respiratory and intrathoracic organs (≥ 60 years, RR 1.38, 95% CI 1.18–1.61). Lymphoid, hematopoietic, and related tissue malignancies were prominent before the age of 30 years, in contrast to breast cancer, which showed a high risk in patients aged 30–59 years. Although not statistical significant, NMSC showed a high rate in the NF1 group before 50 years of age; however, after that age, the risk was reversed.

Fig. 3.

Fig. 3

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Standardized incidence ratio of malignancy in patients with neurofibromatosis type 1 compared with that in the control group according to age and sex.

DISCUSSION

As NF1 is a progressive disorder affecting multiple organs throughout life, patients with NF1 experience prolonged hospital stays because of various comorbidities and malignancies. In this study, we aimed to comprehensively explore hospital use, morbidity, and cancer risk in patients with NF1, particularly according to age group, and to investigate which systemic complications are prominent at different life stages.

In our cohort, the period prevalence of NF1 was approximately 1 in 1,840 individuals, which was higher than the pooled prevalence of 1 in 3,164 individuals (95% CI 1 in 2,132–1 in 4,712) reported in a recent study (13). This difference may be due to early and sensitive detection in Korea, facilitated by regular infant checkups, a registration programme that provides financial support for patients with NF1, and high medical accessibility.

Among non-neoplastic comorbidities, neurological disorders contributed to hospital utilization across almost all age groups in patients with NF1. We reinforced the findings of an American study that observed an increased risk of epilepsy, Parkinson’s disease, and multiple sclerosis (14). The marginally increased rate of headache supports a previous study reported that headache is not specific to NF1 and is not always secondary to NF1-related CNS deformities (15). Considering their chronic and neuropathic nature, however, physicians should pay attention not only to the overt diseases accompanying NF1 but also to non-specific symptoms that affect quality of life (16).

Several psychiatric disorders were also associated with NF1, particularly in pre-adulthood and older ages. Studies have shown early developmental delays in infants with NF1, especially in motor functioning and communication skills (17, 18). Moreover, significant depression and anxiety have been reported in adolescent patients (19). Therefore, early evaluation and intervention may be crucial for improving development and mental health. Regarding older adults, we reaffirmed the high risk of dementia in patients with NF1, consistent with findings from Finnish research (20). Unlike findings from a Danish cohort study, we observed an increased risk of bipolar disorder and schizophrenia in patients with NF1 (21).

To date, it has been noted that respiratory comorbidities of NF1, such as interstitial lung diseases and pulmonary hypertension, primarily appear in adulthood (22). In an Italian study, the increase in mortality because of respiratory diseases was significant only in patients aged > 40 years (3). While controversy remains regarding the true association between interstitial lung diseases, including pulmonary fibrosis, and NF1, we did not find a significant association between these conditions (23). Instead, we recognized a prominent excess of hospital use because of respiratory problems during childhood, which seems to have been underestimated. Accordingly, recent studies have found a common presence of diffuse lung disease in paediatric patients with NF1 and a comparable rate of abnormal structural findings in the lungs, except for pulmonary cysts, between different age groups, including those under the age of 12 (24, 25). Respiratory problems in childhood may not have received attention as a complication of NF1 so far, as NF1 is occasionally diagnosed late because it takes time for affected individuals to meet the diagnostic criteria. Considering the vagueness of symptoms in children, physicians should inform caregivers of the risks and symptoms of respiratory complications.

Conversely, circulatory problems imposed an increased hospitalization burden on older adults. Vasculopathy is a well-known morbidity in patients with NF1 and a Swedish study revealed that hypertension was significantly related to higher mortality (6, 26). However, contrary to respiratory comorbidities, vascular disease was associated with mortality before the age of 29 years but not with the older patients (7). The discrepancy between the impact on mortality and hospital utilization patterns across age groups for respiratory and circulatory complications highlights the importance of the current study, which also analysed medical care use, which, even if it may not directly affect mortality, can have a serious impact on patients’ lives.

Consistent with previous studies, we found a low rate of type 2 diabetes mellitus in patients with NF1 (27, 28). Although the underlying mechanism has not been fully elucidated, the possibility of Ras signalling involvement has been suggested (27). We also recognized a low prevalence of obesity, as previous studies have observed a lower body mass index, particularly in men, than in the general population, possibly owing to altered metabolism (29–32). The reduced prevalence of these risk factors for HCC, as well as that of other risk factors, including alcoholic liver disease and viral hepatitis, may ultimately explain the reduced risk of HCC in this cohort (33). Although previous studies reported a high risk of liver cancer, they included all subtypes of cancer originating from the liver and intrahepatic bile ducts (11, 34). Regarding NMSC, however, considering the low age of first diagnosis in the NF1 group and the higher rate of incidence before age of 50, patients with NF1 seem to be more susceptible to NMSC. We believe that NMSC was less frequently detected in patients with NF1 because of their shorter life expectancy, as the age distribution of NMSC is concentrated in older individuals.

In general, the significant contribution of malignancies to morbidity and mortality in patients with NF1 is well established. Changes in SIR according to age and sex showed similar patterns to those observed in Finnish and French studies, with SIR being greatest before the age of 15 years, higher in women, reversing around the age of 25 years, and then reversing again around the age of 50 (11, 35). Our data also support previous studies that reported an increased incidence of leukaemia in children and a high risk of breast cancer in young women with NF1 (7, 36–38). The significance of the increased risk was lost after the age of 30 years for haematologic malignancies and after the age of 60 years for breast cancer. This suggests the necessity of age-specific screening guidelines for these diseases in patients with NF1. Small intestinal cancer also showed a remarkably high rate, consistent with previous studies (11, 34).

Except for the aforementioned NF1-related malignancies, we analysed the types of cancer that showed a relatively higher rate compared with that of the control group for each age group. We observed the highest risk of malignancy in the adrenal glands in the 0–9 years group. Pheochromocytoma is known to be an NF1-related tumour, and while some cases are malignant, its mean age of onset has been reported to be later than that associated with other genetic diseases (39). Although detailed diagnostic codes could not be identified, the discovery of NF1 gene mutations in a subset of paediatric patients with pheochromocytoma, along with our findings, implies their association from an early age (40). The risk was high for malignancies of the intrathoracic organs in both the 15–19 years and 20–29 years groups, but the specific sites of high incidence differed. Unlike the general population, because the incidence of tumours is high from an early age in patients with NF1, and symptom complaints may be ambiguous at a young age, it is necessary to consider the development of screening criteria based on these results.

Limitations

The main limitations of this study are that it was conducted in a single racial population and that a completely randomly selected general population could not be used as the control. Additionally, surveillance bias may have influenced our findings, as patients with NF1 are likely to undergo more frequent medical evaluations, potentially leading to overestimation of certain RRs. Nevertheless, our additional analysis of outpatient use history, combined with nationwide claims data, enabled detection of even relatively mild complications. This approach provides a more comprehensive understanding of the clinical burden and comorbidity profile of NF1 across different age groups.

Conclusion

NF1 is associated with various non-neoplastic and neoplastic comorbidities, resulting in an increased burden on hospital utilization across multiple diagnostic groups. This study characterized the pattern of organ involvement and malignancies that frequently occurred according to age group, which may benefit physicians in optimizing the management of patients with NF1 suffering from diverse comorbidities.

Supplementary Material

ActaDV-105-43416-s1.pdf (286.8KB, pdf)

ACKNOWLEDGEMENTS

The authors thank Zarathu Co, Ltd for performing the statistical analyses.

Funding Statement

Funding sources This work was supported by the Seoul National University Bundang Hospital Research Fund, 02-2024-0037.

Footnotes

The authors have no conflicts of interest to declare.

IRB approval status

The study was approved by the Institutional Review Board of Seoul National University Bundang Hospital; IRB no. X-2410-930-904.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ActaDV-105-43416-s1.pdf (286.8KB, pdf)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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