2022; 42(3): 314-320
Ann Lab Med 2022; 42(3): 352-357
Published online May 1, 2022 https://doi.org/10.3343/alm.2022.42.3.352
Copyright © Korean Society for Laboratory Medicine.
Genetic Counseling and Long-Term Surveillance Using a Multidisciplinary Approach in von Hippel–Lindau Disease
Sun Joo Yoon, M.D. 1 , Won Kyung Kwon, M.D., Ph.D.1 , Geehay Hong, M.D.2 , Ja-Hyun Jang, M.D., Ph.D.1 , Byong Chang Jeong, M.D., Ph.D.3,4 , Jae Hyeon Kim, M.D., Ph.D.4,5 , and Jong-Won Kim, M.D., Ph.D.1,4
1Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 2bioMérieux Korea, Seoul, Korea; 3Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea; 5Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, and Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Korea
Correspondence to: Byong Chang Jeong, M.D., Ph.D.
Department of Urology, Samsung Medical Center, Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Jae Hyeon Kim, M.D., Ph.D.
Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by variants of the VHL tumor suppressor gene (VHL). Early detection and treatment are essential to prevent morbidity and mortality. We evaluated the effectiveness of surveillance strategies and the utility of a VHL clinic with a multidisciplinary team for the first time in Korea.
Methods: The VHL clinic was organized at the Samsung Medical Center in 2011 and consisted of a multidisciplinary team, including an endocrinologist, urologist, general surgeon, neurosurgeon, ophthalmologist, otolaryngologist, and radiologist. Biochemical and imaging surveillance and personalized genetic counseling were conducted at the VHL clinic and patients were referred to the necessary departments upon detection of disease manifestation. We divided the patients in three groups (I–III) based on their compliance to VHL clinic attendance.
Results: Between 2011 and 2018, 50 VHL patients were identified by VHL molecular analysis and referred to the VHL clinic. Most patients regularly participated in imaging of the central nervous system (43/50, 86.0%) and of the abdomen (46/50, 92.0%). However, there were differences in compliance to determination of the catecholamine level, audiometry, and ophthalmic examination among the three groups.
Conclusions: We present the results of using a multidisciplinary team approach and showed that the VHL clinic strategy is useful for the comprehensive surveillance and management of VHL disease. We hope that VHL clinics will be widely set up in hospitals to improve prognosis in patients with VHL.
Keywords: von Hippel–Lindau (VHL), Multidisciplinary team approach, Genetic counseling, Long-term surveillance
von Hippel–Lindau (VHL) disease is a multisystem cancer syndrome that is caused by variants of the VHL tumor suppressor gene (
There are a few reports on how VHL disease is managed according to current guidelines, such as the VHL Alliance guidelines , but most of these studies have been performed in western populations [7, 9, 14].
We report comprehensive clinical characteristics of Korean VHL disease patients, including age of onset and incidence rate of manifestations, and correlate these with
MATERIALS AND METHODS
Population and procedures
Between May 2011 and May 2018, 54 patients attended the VHL clinic and were diagnosed as having VHL disease based on clinical diagnostic criteria of the Samsung Medical Center (SMC; Seoul, Korea) [1, 15]. Among the 54 patients, two patients passed away due to RCC-associated complications and two patients moved to another center during the study period. For the remaining 50 VHL patients, medical records were reviewed retrospectively. Clinical characteristics, including frequency of each manifestation, age at onset of each manifestation, rate of first onset of each manifestation, and genotype–phenotype correlations, were reviewed and molecular study results were collected after obtaining informed consent. The levels of hormones, such as catecholamine and metanephrine, were evaluated using plasma and urine (spot and/or 24-hour urine) tests.
Each clinical manifestation was categorized based on location as either CNS- or visceral organ-related manifestation. CNS lesions include retinal hemangioblastoma (R-HB), endolymphatic sac tumors (ELSTs), and craniospinal hemangioblastoma (CS-HB). All hemangioblastomas (HBs) located in the cerebral cortex, cerebellum, brainstem, or spinal cord were counted as CS-HBs. Other lesions, except CNS lesions, were included as visceral organ manifestations, including RCC, pancreatic neuroendocrine tumor (PNET), and epididymal cystadenoma. Clinical phenotypes were classified as type 1 or type 2 based on the presence of pheochromocytoma (PCC) [5, 16]. To monitor VHL surveillance, we classified the patients into three groups: group 1, patients who attended the VHL clinic once a year; group 2, patients who attended the VHL clinic once, but did not participate in annual follow-ups; and group 3, patients who were not registered at the VHL clinic, but who visited only the specialists relevant to their clinical manifestations. For patients in group 3, medical records and test results were retrieved through interdepartmental cooperation. The study protocol was approved by the SMC Ethics Review Committee (Institutional Review Board no. 2019-09-072).
Organization of the VHL clinic and surveillance program
We recruited a multidisciplinary team, including an endocrinologist, urologist, general surgeon, neurosurgeon, ophthalmologist, otolaryngologist, and radiologist. In the VHL clinic, we performed
When new clinical manifestations of VHL disease were identified during surveillance, the patient was referred to the appropriate specialist (Fig. 1). Genetic counseling included educating the patient on VHL disease, including inheritance patterns, risk to offspring, and importance of surveillance, and recommendations for VHL screening of other family members.
Figure 1. Departments in a VHL clinic.
Abbreviations: VHL, von Hippel–Lindau; END, department of endocrinology; ENT, department of otorhinolaryngology and head-neck surgery; GS, department of general surgery; NS, department of neurosurgery; OPH, department of ophthalmology; URO, department of urology.
VHL variant analysis
Blood samples were collected from the patients after obtaining informed consent. Genomic DNA was isolated from peripheral blood leukocytes using a Wizard Genomic DNA Purification Kit (Promega, Madison, WI, USA) according to the manufacturer’s instructions. Direct sequencing of the exonic and flanking intragenic regions of all three
Data are expressed as number, percentage, median, or range and were analyzed using MedCalc version 15.5 (MedCalc, Ostend, Belgium) and Microsoft Excel 2010 (Microsoft, Redmond, WA, USA). To compare surveillance attendance, group 1 was considered the main analysis group and comparisons with groups 2 and 3 were made using the Fisher’s exact test. All reported
Patient demographics and clinical manifestations
Of the 50 patients included in the study, 15 (30%) were women, and the median age at onset of VHL disease was 33 years (range: 14–59 years). The median age at first symptom onset was 28 years (range: 14–54 years). The most frequent manifestation was CS-HB (76%, 38/50) and the second most common manifestation was RCC (72%, 36/50). The most frequent manifestation at first onset was CS-HB (46%, 23/50), and the median age at onset of CS-HB was 24 years (range: 16–43 years). Thirty-eight patients (76%) had type 1 VHL and 12 patients (24%) had type 2 VHL. Other demographics of VHL disease are summarized in Table 1.
Among the 23 patients who had CS-HB as a first manifestation, 16 (72%) had symptomatic manifestations, such as blurred vision and high blood pressure that required CT or MRI, compared with seven out of nine patients (85.7%) who had R-HB as a first manifestation. None of the patients (0%, 0/9) who had RCC as a first manifestation were symptomatic, and in 34 out of 36 patients (94.5%) who had RCC or renal cysts as a first manifestation, symptoms were identified incidentally by surveillance. In the case of PNET or pancreatic cysts, surveillance identified cysts in 19 out of the 21 patients. Other clinical characteristics of VHL disease, such as the percentage of symptomatic manifestations that led to first surveillance, are summarized in Table 1.
Missense variants were the most common
Figure 2. Comparison of variant types and genotype–phenotype correlations in VHL types 1 and 2. *Type 1 is characterized by a low risk for pheochromocytoma; †Type 2 is characterized by a high risk for pheochromocytoma.
Abbreviation: VHL, von Hippel–Lindau.
Performance rate of VHL surveillance
We assessed the performance rate of each surveillance test category (Fig. 3). Fifty percent of the patients (25/50) had registered at the VHL clinic. In group 1, all surveillance tests, except the audiometry test (94.4%, 17/18), were conducted once every 12 months (median; range: 2–48 months) (Supplemental Data Table S1). In group 2, catecholamine level determination and ophthalmic examination were conducted less frequently than in group 1 (71.4%, 5/7 vs. 100%, 18/18), although the difference was not significant (
Figure 3. Performance rates of surveillance tests in group 1 (patients who attended the VHL clinic once a year), group 2 (patients who attended the VHL clinic once, but did not participate in annual follow-ups), and group 3 (patients who were not registered at the VHL clinic, but who visited only the specialists relevant to their clinical manifestations).
Abbreviations: CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; US, ultrasonography.
We reviewed the clinical characteristics of VHL disease and the performance rate of VHL surveillance attendance in a Korean population. Although clinical characteristics, such as the frequency of manifestations in patients and age at disease onset, were not distinctively different from those reported in other studies, RCC manifested more frequently than reported in other studies and the age at onset of CS-HB and RCC was lower than in other studied population groups [5, 9, 14, 16]. Most patients with CS-HB (69.6%, 16/23) or R-HB (77.8%, 7/9) as a first manifestation were symptomatic, which led to the first surveillance. In contrast, patients with visceral organ lesions, such as RCC (0%, 0/9), PCC (16.7%, 1/6), and PNET (0%, 0/2), were asymptomatic when these characteristics were observed as a first manifestation.
In most cases, visceral tumors, including RCC (94.5%, 34/36), PCC (80.0%, 12/15), and PNET (90.5%, 19/21), were diagnosed incidentally during surveillance. Therefore, regular surveillance according to the VHL Alliance guidelines is important for the early detection of VHL and especially, visceral organ lesions . Both physicians and patients need to be aware of the possibility of asymptomatic manifestations and, in their own best interest, patients should allow the surveillance of visceral organs, such as the kidneys, adrenal glands, and pancreas.
Like patients in the VHL clinic participant group (group 1), patients in groups 2 and 3, who did not continue yearly follow-ups or did not enroll at the clinic, respectively, regularly received CNS imaging by CT or MRI as well as imaging of the abdomen by CT, MRI, or US (100% vs. 85.7% and 76.0%, respectively). These results show that the patients adhered well to scheduled inspections. However, the performance rates of ophthalmic examination, determination of pheochromocytoma-related hormones (catecholamine, metanephrine, nor-metanephrine, and VMA), and audiometry test were significantly lower in groups 2 and 3. These results suggest that patients do not come to the hospital on a regular basis when they do not experience symptoms.
Only nine patients in group 3 (36.0%, 9/25) received genetic counseling on the importance of surveillance and recommendations for the screening of other family members. Regardless of participation in the VHL clinic, the surveillance interval was not significantly different among patients if they had received each category of surveillance (Supplemental Data Table S1). This implies that physicians tend to be concerned only about their own specialty and that patients only visit the departments relevant to their symptoms. Patients received genetic counseling and were educated on the importance of surveillance if they visited the VHL clinic once, even if they did not participate in annual follow-ups at the VHL clinic. This may explain why no significant differences in the surveillance test performance rates were observed, except for the audiometry test, in patients who attended the VHL clinic, but did not participate in annual follow-ups.
Phenotypic heterogeneity is a hallmark of VHL disease; even within a family harboring the same variant, symptoms are variable . Therefore, comprehensive multidisciplinary surveillance of multiple organs is required to screen for clinical manifestations associated with VHL disease. Surveillance guidelines for VHL disease have been recommended by several VHL study groups [1, 22, 23]. In addition, VHL is inheritable in an autosomal dominant manner and genetic counseling, including education on the inheritance pattern, potential risk to offspring, and reproductive options with family investigation, is required for VHL patients . Although surveillance with genetic counseling is important to detect and manage VHL disease, it is challenging for a physician to conduct all surveillance measures in a timely manner while also providing the patient with comprehensive education . In this respect, a VHL clinic with a multidisciplinary team is extremely useful for conducting comprehensive surveillance for VHL patients. VHL patients require lifelong, continuous management, which can be achieved in a single-center clinic with the multidisciplinary approach suggested here.
Yoon SJ, Kim J-W, Jeong BC, and Kim JH designed the study; Yoon SJ, Kwon WK, Hong G, and Jang J-H collected the clinical samples and analyzed and interpreted the data; and Yoon SJ, Kwon WK, Kim J-W, Jeong BC, and Kim JH wrote and reviewed the manuscript. All authors read and approved the final manuscript.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A2C2002177).
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