Sequential therapy for hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma: a case report and report of a new family pedigree.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal-dominant disorder caused by a heterozygous germline mutation in the fumarate hydratase (FH) gene. HLRCC is clinically characterized by the development of three tumors: uterine leiomyomata, cutaneous leiomyomata, and renal cell carcinoma (RCC). HLRCC-associated RCC is aggressive and diagnosed at a much earlier age than sporadic RCC. It is essential for carriers of HLRCC to undergo annual renal screening by magnetic resonance imaging to detect early stage RCCs. Metastatic HLRCC-associated RCC must be treated by systemic therapy; however, it is unclear which medicines are most effective in treating this cancer owing to its low incidence rate. Immune checkpoint inhibitor (ICI) combinations or ICIs plus tyrosine kinase inhibitors are administered as systemic therapy for clear cell RCC. Here, we report a patient with HLRCC-associated RCC treated with sequential therapy, including ipilimumab plus nivolumab combination and cabozantinib, after diagnosis of HLRCC-associated RCC using FoundationOne Liquid CDx and single-site analysis. We also investigated familial FH mutations and describe a new family pedigree for HLRCC.

Case report: A healthy baby achieved after preimplantation genetic testing from an infertile woman with hereditary leiomyomatosis and renal cell cancer syndrome.

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant inheritable disease caused by Fumarate hydratase (FH) gene germline mutation. It is speculated that for HRLCC infertility women with multiple uterine leiomyomas, preimplantation genetic testing may help block transmission of mutated FH gene during pregnancy. Case presentation: We present the case of a 26-year-old nulligravida with a history of early-onset uterine leiomyomatosis had a heterozygous nonsense mutation [NM_000143.4 (FH): c.1027C > T(p.Arg343Ter)] in the HRLLC gene. After ovulation induction and in vitro fertilization, preimplantation genetic testing for monogenic disorders (PGT-M) on embryos revealed the absence of the pathogenic allele in two blastomeres. Uterine fibroids were identified before embryo transfer, leading to a submucosal myomectomy and long period of pituitary suppression by Gonadotropin-releasing hormone analog (GnRHa). The patient achieved a healthy live birth after the second cycle of frozen-thawed embryo transfer. Conclusion: This case details the successful treatment of an infertile patient with an HRLLC family history, resulting in a healthy birth through myomectomy and PGT-M selected embryo transplantation. Our literature search indicates the first reported live birth after HRLLC-PGT-M.

Fumarate Hydratase-Deficient Renal Cell Carcinoma with Nucleolar Pattern of GATA3 Immunoexpression: Report of 2 Cases.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare aggressive type of renal cell carcinoma. The significant morphologic overlap with other types of renal neoplasia and the limited availability of FH and 2-succinylcholine immunostains for diagnostic use outside large referral centers have created numerous diagnostic pitfalls. As FH-deficient RCC can be associated with hereditary leiomyomatosis and renal cell cancer syndrome, the importance of an accurate diagnosis goes beyond the prognosis and treatment of an individual patient. We present 2 patients with FH-deficient RCC showing a peculiar pattern of GATA3 immunoexpression restricted to tumor nucleoli. If confirmed in further larger studies, this could provide an additional diagnostic clue for considering the FH-deficient RCC diagnosis, and given the frequent papillary morphology and possible hilar location can lead to the misdiagnosis as high-grade urothelial carcinoma, and is an important diagnostic pitfall to be aware of.

Fumarate hydratase-deficient renal cell carcinoma: an oncology care institutional experience.

Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

A new missense mutation c.1240A>G in fumarate hydratase gene leads to uterine leiomyoma associated hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome in Chinese.

OBJECTIVE: This study presents a detailed analysis of the clinical and genetic characteristics of uterine leiomyoma associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), combined with exploration of family history, pathology, and management procedures, supported by thorough evidence collection. METHODS: Blood samples were collected from the proband, and the pathogenic variant was verified using Sanger sequencing. A comprehensive review of family history, FH deficiency pathology, FH and 2SC immunohistochemistry staining was conducted. Functional evidence was derived from clinical and genetic information, supplemented by a literature collection and mutation was reclassified based on ACMG/AMP guidelines. RESULTS: The study successfully identifies a novel missense mutation (c.1240A>G; p.Lys414Glu) in exon 9 of FH, with no prior reports in existing databases. The patient's phenotype and family history, coupled with evidence collected from the literature, contribute to the preliminary determination of the variant as likely pathogenic. We also emphasize that the importance of combining FH-deficient morphology and immunohistochemical staining with 2SC for enhanced sensitivity. CONCLUSION: This research adds a novel missense mutation to the repertoire of FH gene variants, emphasizing its likely pathogenic nature based on a multidimensional analysis of phenotype, family history, and literature evidence. The findings enhance our understanding of the genetic landscape associated with FH and underscore the importance of thorough characterization for accurate variant classification.

Hereditary Renal Cancer Syndromes.

Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel-Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt-Hogg-Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.

Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core "FH-associated" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08 cm, P = 0.01) and associated with younger patients (42.05 vs 47.97, P = 0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5 ± 0.53 vs 3.5 ± 1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P = 0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.

Hereditary Leiomyomatosis and Renal Cell Cancer: A Case Report of Pilar Leiomyomatosis with History of Kidney Cancer and Review of the Literature.

Pilar leiomyoma or piloleiomyoma is a benign neoplasm of the smooth muscle arising from the arrector pili muscle. It manifests as brown to red firm papulonodules with sites of predilection being the face, trunk, and extensor surfaces of the extremities. Histologically, the lesions exhibit ill-defined dermal tumors with interlacing fascicles of spindle cells. Some genodermatoses are characterized by the development of visceral tumors and cutaneous leiomyomatosis such as Reed's syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC). A 55-year-old male presented with reddish-brown papules and nodules on the face and upper back, accompanied by sharp episodic pain on the face. He had undergone nephrectomy for renal cancer 9 years ago, and his younger brother had similar cutaneous manifestation. Histopathologic findings were consistent with pilar leiomyoma, showing bundles of smooth muscle tumors in the dermis. Based on the clinical information including clinical features, past medical history, and family history, HLRCC was highly suspected. To confirm the diagnosis, whole exome sequencing was performed using peripheral blood, which revealed a novel point mutation (c.739G>A, p.Glu247Lys) in the fumarate hydratase (FH) gene. We describe a confirmed case of HLRCC, which is a genetic disorder with a potential to cause visceral cancers, which dermatologists might overlook as a benign condition.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome in a young patient presenting with a large uterus: A case report and review of the literature.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a rare genetic disorder caused by a germline mutation in the fumarate hydratase (FH) gene. It is clinically characterized by cutaneous leiomyomas, uterine leiomyomas and renal cell cancer. A 31-year-old woman presented with severe abdominopelvic pain associated with severe menorrhagia which required a visit to the emergency department. Computed tomography (CT) showed a severe enlargement of the uterus with newly diagnosed fibroids. Magnetic resonance imaging (MRI) confirmed the finding of an enlarged uterus with mild left and moderate right hydronephrosis and hydroureter. The patient tried to manage the pain with oral over-the-counter medications and heat pads without significant relief. She was recommended to proceed with total abdominal hysterectomy and bilateral salpingectomy. She tolerated the procedure well and had an uneventful postoperative recovery. Pathology showed morphologic features, including the staghorn vessels, alveolar edema, eosinophilic cytoplasmic inclusions and prominent nucleoli which are characteristics for FH-deficient leiomyomas. Genetic testing was positive for a pathogenic variant in the FH gene associated with HLRCC. This case highlights the importance of proceeding with genetic testing in patients with personal and family history of leiomyomas and unusual pathology findings. Early identification of the syndrome can lead to appropriate screening for renal cell carcinoma.

Investigating Fumarate Hydratase-Deficient Uterine Fibroids: A Case Series.

Uterine leiomyomas or uterine fibroids are the most common benign soft tissue tumor in reproductive-aged women. Fumarate hydratase deficient (FH-d) uterine fibroids are a rare subtype that is diagnosed only on pathologic evaluation. FH-d uterine fibroids may be the first indicator of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Therefore, identifying and understanding the clinical implication and diagnosis of FH-d uterine fibroids is critical for early diagnosis of HLRCC. This case series investigates the uncommon yet significant condition of FH-d uterine fibroids. We examined the clinical manifestation, diagnostic imaging, and histopathological characteristics of FH-d uterine fibroids in five cases identified at our institution over the last ten years. All diagnoses were confirmed by pathologic evaluation after surgical treatment. Gynecologists and pathologists play a critical role in the early diagnosis of FH-d uterine fibroids and must recognize the relevant clinical and pathologic findings that raise suspicion about this diagnosis. The detection of these cases is largely dependent on the pathologist's ability to recognize unique histopathologic features. Once these characteristics are identified, it should prompt a referral to a gynecologist to consider conducting germline genetic testing. The management of FH-d uterine fibroids necessitates a multidisciplinary approach, including proper genetic screening and regular surveillance, especially for renal tumors.

Fumarase Deficiency and Its Effect on Infertility: A Case Series.

Background: Fumarase deficiency is an autosomal recessive condition characterized by severe neurologic abnormalities due to homozygous mutations in the fumarate hydratase (FH) gene. Heterozygous carriers of FH mutations have increased risk of developing uterine fibroids that can be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). The association between FH mutations and infertility remains uncertain. The objective of our study was to characterize the infertility diagnoses, treatments, and outcomes in women presenting to a fertility center who were found to be carriers of fumarase deficiency based on the presence of heterozygous FH mutations. Case Presentation: A retrospective case series was conducted including 10 women presenting to an academic fertility center who were found to be FH carriers based on genetic carrier screening. Of the 9 women who were engaged in further workup, 2 had imaging results consistent with uterine fibroids. One woman underwent hysteroscopic myomectomy prior to two courses of ovulation induction with timed intercourse (OI/TIC) followed by one successful cycle of IVF. Of the remaining patients, only 1 woman successfully delivered after a cycle of ovulation induction with intrauterine insemination (OI/IUI). Other patients pursuing OI/IUI, OI/TIC, or monitored natural cycles had unsuccessful experiences. Conclusion: Patients with infertility who are offered genetic testing should be screened for FH mutations, as the carriers are at risk of developing HLRCC-associated uterine fibroids, which can influence fertility and pregnancy. Additional research is needed to investigate the impacts of FH mutations on infertility.

Cryptic splice mutation in the fumarate hydratase gene in patients with clinical manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas and risk for development of an aggressive form of papillary renal cell cancer. HLRCC is caused by germline inactivating pathogenic variants in the fumarate hydratase (FH) gene, which encodes the enzyme that catalyzes the interconversion of fumarate and L-malate. We utilized enzyme and protein mobility assays to evaluate the FH enzyme in a cohort of patients who showed clinical manifestations of HLRCC but were negative for known pathogenic FH gene variants. FH enzyme activity and protein levels were decreased by 50% or greater in three family members, despite normal FH mRNA expression levels as measured by quantitative PCR. Direct Nanopore RNA sequencing demonstrated 57 base pairs of retained intron sequence between exons 9 and 10 of polyadenylated FH mRNA in these patients, resulting in a truncated FH protein. Genomic sequencing revealed a heterozygous intronic alteration of the FH gene (chr1: 241498239 T/C) resulting in formation of a splice acceptor site near a polypyrimidine tract, and a uterine fibroid obtained from a patient showed loss of heterozygosity at this site. The same intronic FH variant was identified in an unrelated patient who also showed a clinical phenotype of HLRCC. These data demonstrate that careful clinical assessment as well as biochemical characterization of FH enzyme activity, protein expression, direct RNA sequencing, and genomic DNA sequencing of patient-derived cells can identify pathogenic variants outside of the protein coding regions of the FH gene.

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.

BACKGROUND: HLRCC syndrome is a hereditary cancer predisposition syndrome caused by heterozygous germline pathogenic variant of the fumarate hydratase (FH) gene and characterized by cutaneous leiomyomas (CL), uterine leiomyomas (UL), and renal cell carcinoma (RCC). Loss of function variant of FH gene inactivates the Kreb's cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC. METHODS: Next-generation sequencing (NGS) and Sanger confirmation were given to family members accessible. Following that, a functional study in vitro was performed to further confirm the pathogenicity of the variant. FH-Wild type (FH-WT) and FH-mutant (FH-MUT) (E378K) plasmid were constructed and transfected into 293T and uterine leiomyoma cell lines, respectively. Proliferation assessment was executed to show how this mutation affects the growth of uterine leiomyoma. qPCR and Western blotting were performed to investigate the change of transcription and translation of FH with mutation (E378K), and FH enzyme assay activity were tested in 293T cells with mutation and wild-type plasmids. RESULTS: Here, we presented two families with the same missense variant (c.1132G > A) that has not been reported as a germline mutation in hereditary uterine leiomyomas before and classified as VUS in gene databases. Our in vitro experiments supported the pathogenicity of this missense variant, especially in uterine leiomyomata. CONCLUSIONS: According to the American College of Medical Genetics (ACMG) guideline, the E378K variant was classified as likely pathogenic (with evidence PS4_support, PS3_support, PM2_support, PP1, PP3 and PP4 evidence). Further insights into clinical management in uterine leiomyomata were discussed and should be practiced in gynecological clinical settings.

The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition attributed to pathogenic variants in fumarate hydratase (FH) and presents with cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal cell cancer (RCC). The objective of this study was to characterize the spectrum of clinical and genetic findings in HLRCC at a large academic tertiary care referral center with a focus on dermatologic manifestations. Fifty-seven patients, 41 female and 16 male, with 27 unique pathogenic or likely-pathogenic FH variants were identified from 38 families. Mean age of HLRCC diagnosis was 44.4 years (range 8-82). CLMs were the primary reason for referral in 49.1% (n=28). CLMs were present in 43/56 patients who underwent full skin examination. Three of these 56 patients were diagnosed with cutaneous leiomyosarcoma. Incidence of ULMs was 37/41 female patients; no uterine leiomyosarcomas were observed. RCC was observed in 6/57 patients (mean age of diagnosis: 47.3 years (range 28-79)). CLMs predated RCC in the 3 patients diagnosed with both. Dermatologists have an opportunity to recognize cutaneous manifestations of HLRCC, including cutaneous leiomyomas and rarely cutaneous leiomyosarcomas, and refer for genetic evaluation to provide definitive diagnosis. Identification of HLRCC can promote family cascade testing and screening for RCC.

Navigating the Current Landscape of Non-Clear Cell Renal Cell Carcinoma: A Review of the Literature.

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.

Role of ultra-high b-value DWI in the imaging of hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

PURPOSE: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is associated with an aggressive form of renal cell carcinoma with high risk of metastasis, even in small primary tumors with unequivocal imaging findings. In this study, we compare the performance of ultra-high b-value diffusion-weighted imaging (DWI) sequence (b = 2000 s/mm2) to standard DWI (b = 800 s/mm2) sequence in identifying malignant lesions in patients with HLRCC. METHODS: Twenty-eight patients (n = 18 HLRCC patients with 22 lesions, n = 10 controls) were independently evaluated by three abdominal radiologists with different levels of experience using four combinations of MRI sequences in two separate sessions (session 1: DWI with b-800, session 2: DWI with b-2000). T1 precontrast, T2-weighted (T2WI), and apparent diffusion coefficient (ADC) sequences were similar in both sessions. Each identified lesion was subjectively assessed using a six-point cancer likelihood score based on individual sequences and overall impression. RESULTS: The ability to distinguish benign versus malignant renal lesions improved with the use of b-2000 for more experienced radiologists (Reader 1 AUC: Session 1-0.649 and Session 2-0.938, p = 0.017; Reader 2 AUC: Session 1-0.781 and Session 2-0.921, p = 0.157); whereas no improvement was observed for the less experienced reader (AUC: Session 1-0.541 and Session 2-0.607, p = 0.699). CONCLUSION: The inclusion of ultra-high b-value DWI sequence improved the ability of classification of renal lesions in patients with HLRCC for experienced radiologists. Consideration should be given toward incorporation of DWI with b-2000 s/mm2 into existing renal MRI protocols.

Recurrent Cushing Syndrome From Metastatic Adrenocortical Carcinoma With Fumarate Hydratase Allelic Variant.

Background: Adrenal Cushing syndrome (CS) is usually benign in etiology; however, although rarely, it can be due to adrenocortical carcinoma (ACC); in which case, diagnosis and management are quite complicated. Case Report: A 34-year-old woman presented with worsening confusion, weight gain, new-onset diabetes, and hypertension. Her history was significant for a 7.4-cm left adrenal mass and CS, which were treated with left adrenalectomy 2 years ago. She received hydrocortisone replacement therapy after the surgery, which was discontinued on admission when evaluation showed hypokalemia, hypercortisolemia, and undetectable adrenocorticotropic hormone. Subsequent testing included 1-mg and 8-mg dexamethasone suppression tests, which did not suppress cortisol; late-night salivary cortisol measurement, which yielded a very high salivary cortisol level; and 24-hour urinary cortisol measurement. The level of 11-deoxycortisol was elevated. A computed tomography scan revealed multiple hepatic lesions, which were fluorodeoxyglucose avid, and a biopsy confirmed metastatic ACC. She received treatment with mitotane, metyrapone (later changed to mifepristone), doxorubicin, cisplatin, and etoposide. Over 8 weeks, mitotane levels became therapeutic at 20 mcg/mL, the hepatic masses decreased in size, and she transitioned to adrenal insufficiency and improved glycemic control. Next-generation sequencing of liver biopsy and germline testing revealed a frameshift loss-of-function allelic variant in the FH gene that encodes the protein fumarate hydratase. Discussion: We report a case of recurrent CS due to metastatic ACC in a patient with a previously resected adrenal adenoma and FH allelic variant. Conclusion: Metastatic ACC presenting with severe CS presents a diagnostic and management challenge where combination therapy guided by a multidisciplinary team is essential. FH allelic variant may contribute to ACC progression.