Genotypic and Phenotypic Characteristics of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Korean Patients

Abstract

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.

Family History of Cancers Increases Risk of Renal Cell Carcinoma in a Chinese Population

“…Most of the related literature focused on hereditary patterns of RCC types, such as VHL disease, 19 hereditary papillary RCC, 11 and hereditary leiomyomatosis. 16,20 In our study, we did not come across many familial cases of RCC, although all positive FHs of RCC were found in patients with malignant renal tumors. Instead, we established that FH is an independent risk factor for RCC.…”

“…Our findings are consistent with those of previously published results from other countries in people of other ethnicities. 4 , 13 , 16 However, the importance of positive FH in patients with renal tumors has not yet been discussed thoroughly. Most of the related literature focused on hereditary patterns of RCC types, such as VHL disease, 19 hereditary papillary RCC, 11 and hereditary leiomyomatosis.…”

“… 13 , 14 Studies regarding the association between FH and RCC risk have mostly focused on western populations. 4 , 13 Unfortunately, related research based on an eastern population, such as Japanese 15 or Korean, 16 focused on genotyping and genetic mutations and did not provide explicit data on patients’ epidemiological features.…”

Hereditary leiomyomatosis and renal cell cancer: a case report

“…Выявление новых мутаций FH и описание клинических случаев HLRCC имеют большое значение для медицинских генетиков и онкологов. Такие работы помогают выявлять гено-фенотипические корреляции, классифицировать секвенированные герминальные варианты по степени их патогенности при выполнении прямой ДНК-диагностики HLRCC, описывать частоты мутаций FH в различных популяциях и странах (Южной Корее, Великобритании, Испании и других регионах) [6,15,16]. Отметим, что имеющаяся в анамнезе пациентки феохромоцитома ранее не была описана как характерный признак HLRCC, что не позволяет исключить спорадический характер этого новообразования.…”

A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata

“…Adrenal nodules and pheochromocytomas seem to be additional manifestations while further investigations would still be needed [ 3 , 4 , 5 ]. Cutaneous leiomyomas as one of the most common clinical features presented in over 80% of HLRCC patients, while studies implied that penetrance of cutaneous leiomyomas was low in Japanese, Korean, and Chinese HLRCC patients compared with Caucasians [ 6 , 7 ]. Females usually had uterine leiomyomas at the age of 30–50 years old, while females with HLRCC could develop multiple leiomyomas at a much younger age at 28–32 years old, with large and numerous myomas specifically [ 8 , 9 ].…”