Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

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Abstract

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is an exceptionally rare autosomal dominant condition caused by a germline heterozygous mutation of the fumarate hydratase gene. It manifests as multiple piloleiomyomas, associated with numerous, early-onset uterine leiomyomas in female patients, as well as a highly increased risk of renal cell carcinoma (RCC), most often type 2 papillary RCC. HLRCC has been described in association with adrenal cortical hyperplasia, pheochromocytoma, adrenal cortical carcinoma, and other solid tumors, but the exact relationship between these disorders has not yet been clarified. We present a case of HLRCC associated with bilateral adrenal cortical hyperplasia and discuss the pathogenesis, clinical and paraclinical features of HLRCC, as well as the adequate management of these patients.

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HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.

Jennifer S. Isaacs, Yun Jin Jung, David Mole … (2005)

Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.

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Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.

I Bourdeau, Laurence Amar, Mercedes Robledo … (2014)

Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an 'SDH-like' molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.

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Oxygen homeostasis.

Gregg L. Semenza (2010)

Metazoan life is dependent upon the utilization of O(2) for essential metabolic processes and oxygen homeostasis is an organizing principle for understanding metazoan evolution, ontology, physiology, and pathology. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is expressed by all metazoan species and functions as a master regulator of oxygen homeostasis. Recent studies have elucidated complex mechanisms by which HIF-1 activity is regulated and by which HIF-1 regulates gene expression, with profound consequences for prenatal development, postnatal physiology, and disease pathogenesis.

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Author and article information

Journal

Journal ID (nlm-ta): Rom J Morphol Embryol

Journal ID (iso-abbrev): Rom J Morphol Embryol

Journal ID (publisher-id): RJME

Title: Romanian Journal of Morphology and Embryology

Publisher: Academy of Medical Sciences, Romanian Academy Publishing House, Bucharest

ISSN (Print): 1220-0522

ISSN (Electronic): 2066-8279

Publication date (Print): Apr-Jun 2020

Publication date (Electronic): 18 September 2020

Volume: 61

Issue: 2

Pages: 569-575

Affiliations

[1 ]Department of Dermatology, Elias Emergency University Hospital, Bucharest, Romania; Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

[2 ]Department of Dermatology, Elias Emergency University Hospital, Bucharest, Romania

[3 ]Department of Pathology, Elias Emergency University Hospital, Bucharest, Romania

[4 ]Department of Anesthesiology and Intensive Care, Elias Emergency University Hospital, Bucharest, Romania; Department of Anesthesiology and Intensive Care, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

[5 ]Department of Endocrinology, Elias Emergency University Hospital, Bucharest, Romania; Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Author notes

Corresponding Author: Mara Mădălina Mihai Assistant Professor, MD, PhD, Department of DermatologyElias Emergency University Hospital Carol Davila University of Medicine and Pharmacy 17 Mărăşti Avenue, Sector 1011461 BucharestRomania+4021–316 16 00 mara.mihai@ 123456umfcd.ro

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Publisher ID: 610220569575

DOI: 10.47162/RJME.61.2.29

PMC ID: 7864305

PubMed ID: 33544811

SO-VID: 0574b14a-c61e-4ebc-ada1-bef2d8eff596

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This is an open-access article distributed under the terms of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License, which permits unrestricted use, adaptation, distribution and reproduction in any medium, non-commercially, provided the new creations are licensed under identical terms as the original work and the original work is properly cited.

Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

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Most cited references 54

HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.

Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.

Oxygen homeostasis.

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