Relationship Between Rotavirus P Infection in Korean Neonates and Histo-Blood Group Antigen: a Single-Center Study
2021; 41(2): 181-189
Ann Lab Med 2021; 41(2): 207-213
Published online March 1, 2021 https://doi.org/10.3343/alm.2021.41.2.207
Copyright © Korean Journal of Laboratory Medicine.
Ja Young Seo, M.D., Ph.D.1 , Jeong-Yeal Ahn, M.D., Ph.D.1 , Bhumsuk Keam, M.D., Ph.D.2 , Miso Kim, M.D.2 , Shinkyo Yoon, M.D., Ph.D.3 , Jae Lyun Lee, M.D., Ph.D.3 , Kwonoh Park, M.D., Ph.D.4 , and Inkeun Park, M.D., Ph.D.5
1Department of Laboratory Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea; 2Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 3Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 4Division of Medical Oncology and Hematology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea; 5Division of Medical Oncology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
Correspondence to: Ja Young Seo, M.D., Ph.D.
Department of Laboratory Medicine, Gil Medical Center, Gachon University College of Medicine, 21 Namdong-daero 774 Beon-gil, Namdong-gu, Incheon 21565, Korea
Inkeun Park, M.D., Ph.D.
Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774 Beon-gil, Namdong-gu, Incheon 21565, 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: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome. HLRCC is characterized by the development of cutaneous leiomyomas, early-onset uterine leiomyomas, and HLRCC-associated renal cell cancer (RCC) and caused by germline fumarate hydratase (FH) deficiency. We investigated the genotypic and phenotypic characteristics of Korean patients with HLRCC.
Methods: We performed direct sequencing analysis of FH in 13 patients with suspected HLRCC and their family members. A chromosomal microarray test was performed in female patients with negative sequencing results but highly suspected HLRCC. In addition, we analyzed the clinical characteristics and evaluated the genotype–phenotype correlations in Korean patients with HLRCC.
Results: We identified six different pathogenic or likely pathogenic FH variants in six of the 13 patients (46.2%). The variants included two nonsense variants, two splicing variants, one frameshift variant, and one missense variant. Of the six variants, two (33.3%) were novel (c.132+1G>C, and c.243dup). RCC and early-onset uterine leiomyoma were frequently observed in families with HLRCC, while cutaneous leiomyoma was less common. No significant genotype–phenotype correlation was observed.
Conclusions: We describe the genotypic and phenotypic spectrum in a small series of Korean patients with HLRCC. Our data reveal the unique characteristics of Korean patients with HLRCC and suggest a need for establishing an optimal diagnostic approach for them.
Keywords: FH, Genotype, Hereditary leiomyomatosis and renal cell cancer, Korean, Novel variant, Phenotype
Hereditary leiomyomatosis and renal cell cancer (HLRCC; MIM 150800) is a rare autosomal dominant cancer predisposition syndrome characterized by the variable development of cutaneous leiomyomas, early-onset uterine leiomyomas (fibroids), and type 2 papillary renal cell cancer (RCC), which is now classified separately as HLRCC-associated RCC [1, 2]. HLRCC is caused by germline loss of function variants in the
In Korea, HLRCC and HLRCC-associated RCC have been only recently recognized, and data regarding the treatment outcome of HLRCC-associated RCC in a small series of genetically confirmed Korean HLRCC patients were reported in 2019 [10, 11]. We thus investigated the genetic spectrum of
This study included Korean patients with suspected HLRCC at four academic hospitals in Korea (Gil Medical Center, Asan Medical Center, Seoul National University Hospital, and Pusan National University Yangsan Hospital) between December 2017 and August 2019. The selection criteria for the germline
This study was approved by the Institutional Review Board of Gachon University Gil Medical Center, Incheon, Korea (GAIRB 2017-365). Written informed consent for the study was obtained from all participants.
Fresh peripheral blood samples were obtained and transported, under refrigerated conditions if necessary, to the molecular diagnostic laboratory in Gil Medical Center within 24 hours. We performed direct sequencing of the
The study included 13 probands (seven males and six females) and 19 family members. The demographic and clinical characteristics of the probands are presented in Table 1. Except one, they (12/13, 92.3%) were diagnosed as having RCC (nine papillary type, one mixed papillary and clear cell type, one clear cell type, and one unclassified). One female proband (P12) underwent a hysterectomy at 27 years of age, and a family history of type 2 papillary RCC was documented for her (in her father). Eight of the 13 (61.5%) probands had a family history of HLRCC-associated symptoms. Four of the six female probands had both RCC and uterine leiomyomas, and three of these underwent a hysterectomy before the age of 40 years. In addition, three of the seven (42.9%) male probands had female family members with a history of early-onset uterine leiomyomas. None of the patients in our case series had all three representative HLRCC tumors.
We found six different pathogenic or likely pathogenic
We performed a targeted variant testing in 18 family members of the three probands with pathogenic
All pathogenic and likely pathogenic variants were associated with RCC. Early-onset uterine leiomyomas were documented in all families with pathogenic or likely pathogenic
We identified six families with HLRCC and six pathogenic
In 2011, Smit,
In the female carriers of
HLRCC-associated RCC has distinctive papillary architecture characteristics; however, none of the patients in our study were initially diagnosed as having HLRCC-associated RCC by a pathologist, as it is unknown to pathologists in Korea. In addition to a papillary pattern, a broad spectrum of architectural patterns has been reported for HLRCC-associated RCC, exclusive of clear cell type [7, 21, 22]. Therefore, ancillary tests, such as FH and 2-succinocystein immunohistochemical staining or a somatic/ germline variant test, will be helpful . In a study of germline testing in patients with advanced RCC unselected for inherited syndrome risk factors,
Currently, approximately 100 pathogenic or likely pathogenic
Our detection rate of
This study has potential limitations; it included a small number of patients from only four academic hospitals. Further, no central pathology review was conducted. Finally, sequencing-negative cases were not scrutinized using alternative molecular methodologies.
In summary, we describe the genotypic and phenotypic spectrum in a small series of Korean patients with HLRCC. Our data reveal the unique characteristics of Korean HLRCC patients, and the very low cutaneous leiomyoma penetrance. In addition, our data highlight the need for a more comprehensive approach for diagnosing patients with RCC and uterine/cutaneous leiomyomas who may benefit from tailored treatment and appropriate surveillance for cancer. Further studies on other Korean patients with HLRCC are required to delineate the clinical characteristics and establish a diagnostic strategy.
IP, JLL, BK, and JYS conceived, initiated, and designed the study. IP and JYS performed data analysis and wrote the manuscript. BK, MK, SY, JLL, KP, and IP were responsible for interview, informed consent, and data collection from the study participants. JYS and JYA performed genetic analyses. MK, SY, and KP supervised the study design, and reviewed and commented on the manuscript. All authors read and approved the final manuscript.
No potential conflicts of interest relevant to this paper were reported.