Hereditary Leiomyomatosis and Renal Cell Carcinoma (FH Tumour Predisposition Syndrome)

An autosomal dominant tumour predisposition syndrome caused by heterozygous germline loss-of-function variants in FH, with cutaneous and uterine leiomyomas, fumarate hydratase-deficient renal cell carcinoma and, for specific variants, phaeochromocytoma and paraganglioma; biallelic fumarate hydratase deficiency (fumaric aciduria) is the recessive allelic disorder.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

The association between multiple cutaneous and uterine leiomyomas with dominant transmission was described by Reed, Walker and Horowitz in 1973, in two families in which several members had cutaneous leiomyomas and uterine leiomyomas inherited in an autosomal dominant manner; the association became known as Reed syndrome and, in the dermatological literature, multiple cutaneous and uterine leiomyomatosis [1, 21]. Cutaneous leiomyomas (piloleiomyomas, in the terminology of the 2014 consensus) are rare lesions, histologically composed of bundles of smooth muscle fibres, and GeneReviews considers them highly suggestive of the syndrome; their association with renal cancer would only be described almost three decades later [1, 10].

In 2001, Launonen and colleagues described a Finnish family with 11 members with uterine leiomyomas, two with uterine leiomyosarcoma and seven with a history of skin nodules, two of whom had confirmed cutaneous leiomyomatosis; four women aged between 33 and 48 years had renal carcinoma with distinct papillary histology, presenting as a unilateral, solitary lesion that had already metastasised at diagnosis [22]. Marker analysis localised the gene to 1q, the tumours showed loss of the normal chromosome 1q and the histological features enabled a second family to be diagnosed; the authors named the entity hereditary leiomyomatosis and renal cell cancer (HLRCC) and proposed that the gene was a tumour suppressor [1, 22].

In 2002, the Multiple Leiomyoma Consortium, coordinated by Tomlinson and Aaltonen, identified the gene in the 1q42.3–q43 region: it was FH, which encodes fumarate hydratase (fumarase), an enzyme of the tricarboxylic acid cycle [23]. The leiomyomatosis-associated variants predicted absent or truncated protein or substitutions of conserved amino acids; enzymatic activity was reduced in carriers' lymphoblastoid lines and very low or absent in tumours; and some mothers and fathers of children with recessive fumarate hydratase deficiency also had leiomyomas, showing that heterozygotes and homozygotes or compound heterozygotes have distinct phenotypes [23]. In 2003, Toro and colleagues found FH variants in 31 of 35 North American families (89%), with 98% of women with cutaneous leiomyomas also having uterine leiomyomas, 44% of hysterectomies performed by 30 years of age, and unilateral, solitary renal tumours of papillary type II or collecting duct type [24].

The spectrum broadened over the following decades. In 2014, Castro-Vega and colleagues identified germline FH variants in five of 598 patients with phaeochromocytoma or paraganglioma without a variant in known genes, with more frequent metastatic phenotype and multiple tumours [25], and Clark and colleagues described catalytically inactive missense variants, one in a paediatric phaeochromocytoma [26]. In the same year, the international symposium held in Paris in 2013 published the first consensus on renal risk, surveillance and treatment [10]. GeneReviews adopted the name “FH tumour predisposition syndrome”, recognising that germline FH variants predispose to several tumour types [1], and the 2022 WHO classification incorporated FH-deficient RCC among molecularly defined renal carcinomas, abandoning the subdivision of papillary carcinomas into types 1 and 2 that had been the principal warning sign for the syndrome for two decades [11, 12].

This article covers the heterozygous FH tumour predisposition syndrome and describes biallelic fumarate hydratase deficiency as an allelic disorder and metabolic differential diagnosis, of direct relevance to counselling heterozygous relatives. The hereditary paraganglioma-phaeochromocytoma syndromes associated with the SDHx genes, in which FH is a minor gene, are not developed; only the FH variants associated with phaeochromocytoma and paraganglioma and the surveillance they warrant are described.

2. Molecular Genetics and Pathophysiology

2.1 The FH gene and the two fumarate hydratase isoforms

The FH gene is located at 1q43 and encodes fumarate hydratase (EC 4.2.1.2), an enzyme whose active form is a homotetramer and which catalyses the reversible hydration of fumarate to L-malate in the tricarboxylic acid cycle (Krebs cycle) [1, 3]. A single gene gives rise to a mitochondrial and a cytosolic isoform [27, 28]. The mitochondrial isoform is part of the Krebs cycle and is required for efficient oxidative phosphorylation; the cytosolic isoform metabolises fumarate produced in the urea cycle, the purine nucleotide cycle and arginine synthesis [28]. GeneReviews notes that the reference sequence corresponds to the mitochondrial isoform of 510 amino acids, but that some literature and locus-specific databases number variants according to the cytosolic isoform of 467 amino acids; an alternative transcription initiation mechanism has been proposed to explain the two isoforms, instead of the alternative translation initiation previously assumed [1].

This dual numbering has practical consequences. The founder variant described in English and German families, published as R58P, corresponds in current numbering to NM_000143.4:c.302G>C, p.(Arg101Pro); p.Arg58Pro is its historical name in the cytosolic isoform [1, 29]. The description c.302G>C → p.(Arg101Pro) in transcript NM_000143.4, the MANE Select transcript, and its genomic coordinate NC_000001.11:g.241513679C>G were confirmed in VariantValidator [4]. The most frequent variant in recessive deficiency, NM_000143.4:c.1431_1433dup, p.(Lys477dup), appears in the literature as 1302insAAA, 435insAAA, 435insK, 1433insAAA and insK477 [4, 28].

2.2 Inheritance and disease mechanism

FH tumour predisposition syndrome is inherited in an autosomal dominant manner and the mechanism is loss of function [1]. Germline variants, together with somatic variants and loss of heterozygosity in tumour tissue, indicate that the tumour arises after inactivation of both alleles [1, 23]. The Saudubray chapter on Krebs cycle defects emphasises that, as in succinate dehydrogenase deficiency, loss of enzymatic activity is observed only in tumour tissue, because it results from the combination of the heterozygous germline variant with somatic loss of the other allele — a mechanism that the book compares with that of focal forms of hyperinsulinism [27]. Alam and colleagues showed that truncating variants are functionally null alleles and that disease-associated missense variants affect conserved residues, particularly at the active or activation site, with no correlation between variant type or location and phenotype [30].

2.3 Fumarate as an oncometabolite

FH-deficient RCC involves impaired oxidative phosphorylation and a shift towards aerobic glycolysis (the Warburg effect) [1, 31]. AMP-activated protein kinase (AMPK) levels are reduced, with reduced p53, decreased iron transporter DMT1 and low cellular iron levels, and increased fatty acid synthesis [31]. Accumulated fumarate and reduced iron inactivate prolyl hydroxylases, stabilising HIF-1α and increasing expression of genes such as those encoding vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1) [31]. In 2005, Isaacs and colleagues demonstrated that fumarate is a competitive inhibitor of HIF prolyl hydroxylase and that biallelic FH loss coincides with HIF overexpression in renal carcinoma [7]. Xiao and colleagues showed that fumarate and succinate competitively inhibit several α-ketoglutarate-dependent dioxygenases — histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases and TET 5-methylcytosine hydroxylases — with global alteration of histone and DNA methylation [32]. This mechanism explains the CpG island methylator phenotype (CIMP) described in FH-associated tumours: all renal tumours from patients with HLRCC (and with SDHB variants) showed CIMP, with extensive, relatively uniform hypermethylation and silencing of genes in the HIF (HIF3A, CITED4), WNT (SFRP1) and epithelial–mesenchymal transition (OVOL1) pathways [8]. The Cancer Genome Atlas (TCGA) consortium had already identified, among type 2 papillary carcinomas, a CIMP subgroup characterised by FH variants and reduced survival [12].

Fumarate also covalently modifies cysteine residues, forming S-(2-succino)cysteine (2SC), a process termed protein succination [6]. Bardella and colleagues showed that 2SC is abundant in murine models with Fh1 loss and in 16 tumours from patients with HLRCC, and undetectable in 200 normal tissues and 1,342 tumours of types unrelated to HLRCC; this finding established the basis for the 2SC immunohistochemistry now used in diagnosis [6]. A third consequence was described in 2018: fumarate and succinate suppress DNA repair by homologous recombination, making tumour cells vulnerable to poly(ADP-ribose) polymerase (PARP) inhibition in preclinical models, leading the authors to consider HLRCC and SDH syndromes as familial DNA repair deficiency syndromes [33].

The genomic profile of FH-deficient RCC was characterised in 25 untreated primary tumours: low somatic mutational burden (median 0.58 mutations per megabase), frequent copy-number alterations, CIMP in most cases and infiltration by T lymphocytes with high expression of immune checkpoint molecules, including programmed cell death protein 1 ligand 1 (PD-L1) [1, 34]. Approximately 20% of tumours, with lower metastatic potential, showed relatively low methylation, indicating heterogeneity within the entity [34].

2.4 Variant spectrum and genotype–phenotype correlations

FH variants are distributed throughout the coding region. In the North American families described by Toro and Wei, 31 different variants were identified in 56 families (20 missense, eight frameshift, two nonsense and one splice variant), with a detection rate of 93% in families with clinical suspicion [24, 35]. In the Spanish series of 197 individuals, carriers of missense variants had a higher frequency of cutaneous leiomyomas, uterine leiomyomas and renal cysts than carriers of loss-of-function variants [36]. For renal risk, neither the 2014 consensus nor the Kamihara cohort found a difference between truncating and non-truncating variants [10, 37].

The relevant correlations concern three groups of variants. The first comprises variants associated with phaeochromocytoma and paraganglioma, predominantly missense, listed in GeneReviews using NM_000143.4 and Human Genome Variation Society (HGVS) nomenclature: c.157G>A p.(Glu53Lys), c.220A>T p.(Arg74Ser), c.268-2A>G, c.349G>C p.(Ala117Pro), c.580G>A p.(Ala194Thr), c.700A>G p.(Thr234Ala), c.816_836del21 p.(Ala273_Val279del), c.908T>C p.(Leu303Ser), c.986A>G p.(Asn329Ser), c.1142C>T p.(Thr381Ile) and c.1301G>A p.(Cys434Tyr) [1]. Carriers of these variants are less likely to have manifestations of HLRCC or fumarate hydratase deficiency, although overlap has been reported [1, 38]. The second group comprises variants that, when biallelic, cause fumarate hydratase deficiency without increasing the risk of HLRCC-associated tumours in heterozygotes: c.521C>G p.(Pro174Arg), c.923C>G p.(Ala308Gly), c.1127A>C p.(Gln376Pro) and c.1431_1433dup p.(Lys477dup) [1, 37]. In the Memorial Sloan Kettering cohort, the p.Lys477dup duplication was detected in 24 of 7,571 patients with cancer, none with renal carcinoma, and none of the 372 patients with renal cancer had it [39]; in Kamihara's laboratory cohort, carriers of variants associated only with recessive deficiency had a cancer profile similar to that of controls without a variant, whereas carriers of the remaining pathogenic variants had more renal cancer (odds ratio 7.6 versus controls) and at an earlier age (median 35 years) [37]. The third group comprises founder variants, described in section 9.

In 2025, the British CanVIG-UK consortium quantified the weight of phenotype in the classification of rare FH variants, comparing 387 individuals with HLRCC and 1,780 with renal cancer with 562,295 population controls; likelihood ratios were much higher for the HLRCC phenotype (2 669.4 for truncating and 214.7 for missense variants) than for isolated renal cancer (95.5 and 5.8), and three missense variant hotspots were identified [40]. These values are intended for applying PP4/PS4 criteria within the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) framework and show that isolated RCC provides much weaker phenotypic evidence than the typical syndrome combination.

2.5 Recessive allelic disorder: fumarate hydratase deficiency

Biallelic FH variants cause fumarate hydratase (fumarase) deficiency, also called fumaric aciduria, an autosomal recessive Krebs cycle disorder with fewer than 100 patients reported [27, 28]. The enzymatic block impairs energy production and causes secondary inhibition of other enzymes through accumulation of proximal metabolites (fumarate, succinate, α-ketoglutarate and citrate) [27]. Based on the observed genotypes, complete loss of enzymatic activity is probably incompatible with life [28]. The c.1431_1433dup p.(Lys477dup) variant accounts for approximately 30% of deficiency-associated pathogenic variants [28]. The shared gene explains why heterozygous relatives of children with deficiency may be at risk of HLRCC, a topic developed in sections 6 and 8.

3. Clinical Spectrum and Manifestations by System

3.1 Overview and limitations of published frequencies

The syndrome is characterised by cutaneous leiomyomas, uterine leiomyomas and renal tumours; patients usually have multiple cutaneous leiomyomas, one or more uterine fibroids and one or no renal tumour, and rarely multifocal or bilateral renal tumours [1]. The frequencies in Table 1 derive from cohorts of individuals with an identified variant, mostly assessed because of clinical manifestations or family history; GeneReviews cautions that these values probably overestimate frequencies and that manifestations may be milder in carriers identified through population screening or incidental findings [1]. The higher-than-expected carrier frequency estimate suggests that many carriers remain unrecognised and that, with more population-based testing, the phenotypic spectrum will broaden [1, 9].

Comparison between cohorts illustrates the ascertainment effect: in a review of 672 patients published up to 2019, mainly case reports and series, cutaneous leiomyomas occurred in 71.5%, uterine leiomyomas in 83% of women and RCC in 34.9%, figures higher than those of national cohorts with family cascade testing [44].

3.2 Skin

Cutaneous leiomyomas present as firm papules or nodules, skin-coloured to light brown or reddish, distributed over the trunk and limbs and, occasionally, the face and neck; they are generally multiple and may be clustered, segmental or disseminated [1]. Histological examination shows bundles of smooth muscle fibres with central, elongated, blunt-ended nuclei [1]. They usually appear between the second and fourth decades, some as early as childhood, and increase in size and number with age; many patients describe pain or sensitivity to cold or touch [1]. Orphanet gives the usual onset age as approximately 25 years (range 10–47) [2]. In the Netherlands, all carriers older than 40 years had cutaneous leiomyomas [45]. The Oxford book includes the syndrome in the differential diagnosis of skin “nodular lesions”, highlighting that heterozygous FH variants were found in approximately 75% of clinical HLRCC cases in Alam's series [30, 46].

Cutaneous leiomyosarcoma has been reported in carriers (three cases in the French series and three of 56 patients in the Michigan series) [42, 43], but GeneReviews notes that, because of changes in diagnostic criteria and nomenclature, some lesions previously called leiomyosarcomas would correspond to atypical smooth muscle neoplasms or leiomyomas [1]. The AACR paediatric recommendation states that malignant transformation of cutaneous leiomyomas, although infrequent, occurs in adults and that carriers should be advised to seek assessment for rapid growth or other changes [13].

3.3 Uterus and female reproductive tract

Women with the syndrome have more fibroids and earlier onset than the general population; the mean identification age is approximately 30 years and fibroids are associated with abdominal pain, irregular menstruation and menorrhagia [1]. In a North American case–control study of 105 women from HLRCC families, FH variant carriers had an increased risk of fibroids (odds ratio 7.6; 95% confidence interval, 95% CI, 2.9–20.0) and a median diagnostic age of 28 years, versus 38 years in non-carriers [47]. In the French series, 59 of 114 women (52%) underwent myomectomy or hysterectomy, at a median age of 35 years (range 25–58) [1]. In the Netherlands, 11 of 21 female carriers had undergone surgery for symptomatic fibroids, at a mean age of 35 years [45].

FH-deficient uterine leiomyomas have characteristic morphology: alveolar-pattern oedema and “staghorn” vessels at low magnification, and cells with a halo-surrounded macronucleolus and cytoplasmic eosinophilic globules at high magnification; they are frequently classified as having atypical histology, with bizarre nuclei [1, 48]. They usually show loss of FH expression and positive cytoplasmic staining for 2SC [1]. Uterine leiomyosarcoma has been reported (two cases in the original Finnish family; standardised incidence ratio of 71 in Finnish families) [22, 49], but GeneReviews applies the same nosological caveat as for cutaneous leiomyosarcoma, and neither the French nor Michigan series observed uterine sarcomas [1, 42, 43]. FH-deficient uterine leiomyomas also occur sporadically, through somatic biallelic inactivation [1, 50].

3.4 Kidney

The renal tumour is the manifestation determining prognosis. It is usually unilateral and solitary, although it may be multifocal or bilateral; it may cause haematuria, loin pain or a palpable mass, but many patients are asymptomatic [1]. The histological spectrum includes papillary carcinoma (described before 2022 as type 2), undefined papillary, unclassifiable, tubulocystic and collecting duct carcinoma [1]. In the series of 40 tumours from 38 patients from families with a confirmed variant, ages ranged from 17 to 75 years, tumours measured 2.3 to 20 cm, were unilateral in all but two, and showed papillary (25), tubulopapillary (8), tubular (2) and solid (1) patterns, with the distinctive finding of a large nucleus with a prominent eosinophilic inclusion-like nucleolus surrounded by a clear halo [51]. This finding, however, is not specific: it was present in 23 of 24 carcinomas from carriers, but also in 58% of type 2 papillary carcinomas without an FH alteration [52].

Aggressive behaviour was described from the earliest series. Among 19 National Cancer Institute patients, four of seven with T1 tumours measuring 2.0 to 6.7 cm already had nodal spread or metastases at nephrectomy, and 47% had nodal or distant disease [53]. In the French series, 82% of RCCs were metastatic at diagnosis or metastasised rapidly, with a median survival of 18 months (95% CI 11–29) in metastatic disease [42]. In the British cohort of 185 individuals from 69 families, the mean age at diagnosis of symptomatic RCC was 44 years, median survival was 21 months and mean survival was 15.8 months for stages III–IV versus 80.7 months for stages I–II [1, 41]. The European Association of Urology (EAU) guidelines state that more than 75% of cases are staged as pT3–4 at nephrectomy [14].

The age distribution has implications for surveillance. In the 2014 consensus review, the mean diagnostic age of 103 cases with known age was 41 years (11–90), with 7% before 20 years; in the larger series, 3 of 74 patients (4%) had RCC before 20 years, and the authors acknowledged possible publication bias towards very early cases [10]. The AACR review identified 15 children and adolescents with HLRCC-associated RCC, all in the second decade except one case aged 7 years [13]. The 11-year-old child described by Alrashdi was diagnosed at the first surveillance examination following identification of the familial variant [54].

3.5 Phaeochromocytoma and paraganglioma

Germline FH variants have been identified in patients with phaeochromocytoma and paraganglioma (PCC/PGL), with somatic loss of the second allele, low 5-hydroxymethylcytosine levels and positive 2SC staining in tumours, an epigenetic pattern similar to that of tumours with SDHB variants [25]. In a laboratory registry of 120,061 people tested, PCC/PGL prevalence was 22.2% among carriers of variants previously associated with PCC/PGL, versus 0.9% in those testing negative; carriers of classical HLRCC variants (0.3%) and recessive deficiency variants (1.4%) did not have increased prevalence [38]. Among 319 Chinese patients with PCC/PGL, Ma and colleagues described a germline variant in a family with PCC/PGL and somatic mosaicism (c.206G>A, p.Gly69Asp, 5% allele fraction in blood) in a woman with phaeochromocytoma and uterine leiomyomas [5]. The Oxford book's table of genetic causes of phaeochromocytoma already included FH, alongside RET, SDHx, VHL and NF1 [55].

3.6 Other tumours

Neoplasms whose relationship to the syndrome is not established have been described in other carriers; GeneReviews considers further data necessary [1]. In the Finnish families, breast and bladder carcinomas showed biallelic FH inactivation, and atypical uterine leiomyomas, renal cysts and adrenal adenomas were observed [49]. The HLRCC Alliance commentary adds adrenal nodules and Leydig cell tumours [11], and the EAU guidelines list adrenal nodules among extrarenal manifestations [14].

4. Clinical Recognition and Warning Signs

Suspicion should arise with any combination, in the personal or family history, of cutaneous leiomyomas, numerous, large or early-onset uterine fibroids and a renal tumour with the described features, and also with tumours showing characteristic histology, even without other signs [1]. Absence of family history does not exclude the diagnosis, owing to the possibility of a de novo variant, variable expressivity or reduced penetrance [1]. The following warning signs summarise the indications in the sources consulted.

Directed clinical examination includes skin inspection for leiomyomas, recommended by the Oxford book when assessing any patient with RCC and patients with phaeochromocytoma [55, 56]. Cutaneous leiomyomas preceded RCC in the three Michigan series patients with both manifestations, and skin findings prompted referral in 49.1% of cases, placing the dermatologist in a position to detect the disease early [43].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Proposed clinical criteria and molecular diagnosis

In 2011, the Dutch group proposed clinical criteria for probable diagnosis: multiple histologically confirmed cutaneous leiomyomas, or at least two of the following — surgical treatment of symptomatic fibroids before 40 years, type 2 papillary carcinoma before 40 years or a first-degree relative meeting one of these criteria; collecting duct carcinoma before 40 years was suggested as an additional subtype [10, 45]. The Orphanet summary, revised in 2014, bases diagnosis on multiple cutaneous leiomyomas with at least one histologically confirmed, or a solitary leiomyoma with a positive family history [2]. These criteria have never been prospectively validated, and definitive diagnosis requires molecular testing [1].

Diagnosis is established in a proband with a heterozygous pathogenic or likely pathogenic FH variant; a variant of uncertain significance neither establishes nor excludes the diagnosis [1]. When phenotype and histology suggest the syndrome, GeneReviews recommends a multigene panel including FH and differential diagnosis genes, or single-gene testing with sequencing and deletion/duplication analysis; when the phenotype is atypical, exome or genome sequencing does not require the clinician to select the gene [1]. For non-syndromic RCC cases, the Oxford book proposes panels including VHL, MET, FLCN, SDHB, FH and BAP1 and karyotyping for constitutional chromosome 3 translocations [56]. Orphanet also notes that FH enzymatic activity is reduced in fibroblasts or lymphoblastoid cells, and Alam and colleagues showed that the biochemical assay identifies carriers with high sensitivity and specificity and detects reduced activity in some patients without an identified variant [2, 30]; in current practice, however, diagnosis of the dominant form has no non-molecular confirmatory test [3].

5.2 Performance and limitations of germline testing

The table values refer to the proportion of variants recorded in the Human Gene Mutation Database (HGMD) detectable by each method and do not equate to the clinical sensitivity of testing [1]. The detection rate in families with clinical suspicion ranges from 76% to 100% in the series compiled by the 2014 consensus [10], was 89% and subsequently 93% in North American families [24, 35] and 14 of 33 referred families in the Netherlands, where MLPA was included and a whole-gene deletion was identified [45]. A negative test does not exclude the syndrome in a convincing phenotype: GeneReviews acknowledges the need for more data on follow-up of families with strong clinical suspicion without molecular confirmation, and the 2014 consensus indicates that tumour immunohistochemistry may support diagnosis in these families [1, 10]. Somatic mosaicism has been demonstrated (5% allele fraction in blood in a woman with phaeochromocytoma and uterine leiomyomas) and should be considered when interpreting results [1, 5].

The report should state the gene, versioned transcript (NM_000143.4, MANE Select), DNA and protein HGVS nomenclature, zygosity, ACMG/AMP classification and methodological limitations [1, 4]. When the literature uses cytosolic isoform numbering, both designations should be provided, as in c.302G>C p.(Arg101Pro), historically p.Arg58Pro [1]. Interpretation of rare missense variants benefits from CanVIG-UK quantitative data, which distinguish the weight of the full HLRCC phenotype from isolated renal cancer [40]. A variant of uncertain significance does not become pathogenic through therapeutic response or partial segregation; segregation analysis and tumour immunohistochemistry are tools for investigating the variant.

For variants identified in a tumour, the ESMO genomics handbook recommends that tumour-only sequencing be followed by germline testing when a variant is found in a predisposition gene such as FH, FLCN, TSC1/TSC2 or SDH genes [12]; the EAU guidelines emphasise that only germline testing establishes whether a tumour variant is constitutional [14].

5.3 Who to test

These criteria have an empirical basis. In a prospective cohort of 254 patients with advanced RCC (stages III–IV) undergoing germline sequencing, 16.1% had germline variants, FH was the second most frequent gene (seven patients) and 35.7% of carriers of variants in RCC genes did not meet the testing criteria then in force; among non-clear cell carcinomas, 11.7% had a variant in an RCC-associated gene [57].

5.4 FH/2SC immunohistochemistry and pathological diagnosis

The 2022 WHO classification incorporated FH-deficient RCC among molecularly defined renal carcinomas, entities with heterogeneous morphology that cannot be diagnosed by morphology alone [11, 12]. The tumour usually displays several mixed patterns (papillary, tubular, solid, tubulocystic and even low-grade oncocytic), leading to classifications such as unclassifiable; the eosinophilic macronucleolus is frequent but non-specific [11, 52].

The HLRCC Alliance commentary, in collaboration with the European Renal Association's Genes & Kidney group, the ERKNet, eUROGEN and GENTURIS European Reference Networks, the European Society of Pathology uropathology group and the International Kidney Cancer Coalition, recommends combined use of both markers and proposes 2SC as a reflex test in high-grade non-clear cell tumours, papillary tumours with mixed patterns, tubulocystic tumours, eosinophilic tumours and cases with an inactivating FH variant detected by tumour sequencing [11]. Immunohistochemistry does not distinguish the germline syndrome from a tumour with biallelic somatic FH inactivation, so germline testing remains necessary [1].

5.5 Screening through the uterus

Uterine fibroids are the most frequent entry point in women. In a five-year prospective programme assessing 2,060 women with uterine smooth muscle tumours, morphology suggestive of FH deficiency was described in 30 (1.4%); ten underwent germline testing and six had a variant (five pathogenic, one of uncertain significance), corresponding to an HLRCC diagnosis in 0.24% of all women; two of the five carriers of pathogenic variants had normal FH immunostaining, both with missense variants [48]. In a six-year morphological screening programme involving 1,838 tumours, 71 (3.9%) had suggestive morphology, 41 had confirmed FH loss and 5 of 19 women tested (26%) were germline carriers [59]. In a Chinese series of 252 FH-deficient fibroids with paired tumour–normal sequencing, 35.7% (74/207) were hereditary, the remainder somatic; hereditary cases occurred before 45 years and were associated with more infertility, multifocality, operations and familial clustering, and the authors proposed universal FH/2SC immunohistochemistry in fibroids with at least three morphological features of deficiency [60]. Targeted sequencing of FH-deficient fibroids estimated that only 2.7–13.9% of women with these tumours would be germline carriers [50]. GeneReviews also refers to two recent series in which fewer than 40% of women with atypical or FH-deficient fibroids went on to undergo germline testing [1].

5.6 Initial assessment after diagnosis

ClinGen assessed syndrome actionability for the outcome “morbidity and mortality from HLRCC-associated RCC” with the intervention “specialist assessment and surveillance”: a score of 10CC in adults (severity 2, likelihood 2C, effectiveness 3C, nature of intervention 3) and 8CC in the paediatric setting (severity 2, likelihood 1C, effectiveness 2C, nature 3), both published on 20 September 2023 [20]. GeneGuidance records that the experts agreed with the calculated classification, with reservations about the scarcity of data on intervention effectiveness [3].

6. Differential Diagnosis

6.1 Hereditary RCC syndromes

Each hereditary RCC syndrome is associated with characteristic renal histology, and all syndromes in the table are autosomal dominant [1]. The table incorporates GeneReviews, Table 4.23 of the Oxford book and Table 8.1 of the EAU guidelines.

SDH-deficient RCC is the closest pathological differential diagnosis, because it also results from a Krebs cycle defect and displays CIMP, although less uniformly [8]. Its aggressiveness is generally lower: the EAU guidelines give a metastatic risk of 12%, except in high-grade tumours, where it is approximately 70% [14].

6.2 Skin lesions

Cutaneous leiomyomas are rare and highly suggestive of the syndrome, but clinically resemble other lesions, so diagnosis requires histology [1]. The Oxford book includes them in the genetic differential diagnosis of nodular lesions, alongside neurofibromas in neurofibromatosis type 1, familial lipomas, steatocystoma multiplex (KRT17), Brooke-Spiegler syndrome and multiple cylindromatosis (CYLD) [46]. Distinguishing the fibrofolliculomas of Birt-Hogg-Dubé syndrome from leiomyomas is the basis for the skin examination recommended in all patients with RCC [56].

6.3 Uterine fibroids

Uterine fibroids are the most frequent benign pelvic tumour in the female population and, in most cases, are not associated with other tumours [1]. Atypical histology and FH loss with positive 2SC should prompt germline testing, bearing in mind that most FH-deficient fibroids are sporadic [1, 50, 60].

6.4 Fumarate hydratase deficiency and other causes of fumaric aciduria

Biallelic fumarate hydratase deficiency usually presents as severe neonatal or early-infantile encephalopathy, with failure to thrive, hypotonia, lethargy and seizures, facial dysmorphism (frontal bossing, depressed nasal bridge, hypertelorism), microcephaly in approximately one-third and brain MRI abnormalities (atrophy, ventriculomegaly, bilateral polymicrogyria, delayed myelination, corpus callosum abnormalities and small brainstem) [27, 28]. Prenatal manifestations include polyhydramnios, congenital hydrocephalus and preterm delivery [27]. The GeneReviews table reports developmental delay or intellectual disability in 100%, hypotonia in 68%, seizures in 43% and abnormal brain imaging in 92%; milder forms with prolonged survival have been described [28].

The key biochemical finding is an isolated increase in urinary fumaric acid, sometimes with increased succinic acid and α-ketoglutarate; increased succinyladenosine in urinary purines and pyrimidines completes the highly suggestive pattern, and enzymatic activity can be measured in leucocytes or fibroblasts (often below 10% of the control mean in severe cases, 11–35% in some patients) [27, 28]. Transient fumaric acid excretion is common in infants and occurs in infants under metabolic stress, as in heart failure due to severe congenital heart disease, so testing should be repeated when stable; increased fumarate with other Krebs cycle intermediates occurs in mitochondrial disorders, such as Leigh syndrome, and pyruvate dehydrogenase complex deficiency [28]. There is no specific treatment; the ketogenic diet is usually considered contraindicated for epilepsy in Krebs cycle defects, although one patient given an early high-fat, low-carbohydrate diet had a milder course [27]. Protein restriction produced neither clinical nor biochemical improvement [28].

The relevance to this article lies in heterozygotes. Most heterozygous parents are healthy, but cutaneous leiomyomas, fibroids and renal carcinoma have been reported in heterozygous relatives of affected children, and the deficiency GeneReviews considers lifelong renal surveillance appropriate for these heterozygotes [28]. The decision depends on the variant: variants associated only with the recessive form, such as p.Lys477dup, have not shown increased renal cancer risk in heterozygotes [37, 39], and AACR explicitly distinguishes this variant [13]. AACR adds that leiomyomatosis and RCC have not been reported in patients with the recessive form, which may reflect the rarity of the disease (approximately 50 cases reported at that time) and short survival [13].

7. Treatments and Risk Management Strategies

7.1 Principles

There is no specific preventive treatment for the syndrome; care rests on renal surveillance, early excision of renal tumours, symptomatic treatment of cutaneous and uterine leiomyomas and systemic treatment of advanced disease [1, 11]. Management is multidisciplinary and should involve professionals familiar with the syndrome, particularly a urological oncology surgeon [1, 2]. No medicine has authorisation from the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA) with a specific indication for the syndrome or FH-deficient RCC [16, 18].

7.2 Cutaneous leiomyomas

Cutaneous leiomyomas should be assessed by a dermatologist [1]. Surgical excision is standard treatment for solitary or few symptomatic lesions; carbon dioxide laser, cryotherapy and electrodesiccation are alternatives, and recurrence rates are high [1]. Medicines are adjuncts for pain and include vasodilators (nitroglycerin, nifedipine, phenoxybenzamine, doxazosin) and neuropathic pain medicines (gabapentin, pregabalin, duloxetine) [1, 2]. No label includes pain from cutaneous leiomyomas; the following doses are those of the labels in the closest indications (neuropathic pain for the gabapentinoids and duloxetine; hypertension, angina or phaeochromocytoma for the vasodilators), applied by extrapolation and off-label. Gabapentin (Neurontin®): 300 mg on day 1, 300 mg twice daily on day 2 and 300 mg three times daily on day 3, with increases of 300 mg/day every 2–3 days up to a maximum of 3,600 mg/day in the Portuguese SmPC for peripheral neuropathic pain in adults; the FDA label, in post-herpetic neuralgia, titrates up to 1,800 mg/day and showed no additional benefit above this dose [61, 62]. Pregabalin (Lyrica®): 150 mg/day in 2 or 3 divided doses, 300 mg/day after 3–7 days and a maximum of 600 mg/day after a further 7 days in the European SmPC (peripheral and central neuropathic pain in adults); the FDA label limits the dose to 300 mg/day in diabetic neuropathy and allows 600 mg/day in post-herpetic neuralgia [63, 64]. Duloxetine (Cymbalta®): 60 mg once daily in diabetic peripheral neuropathic pain in adults, with a maximum of 120 mg/day in divided doses in the European SmPC and of 60 mg/day in the FDA label [65, 66]. Prolonged-release nifedipine (Adalat CR®): in adults with hypertension or angina, 30 mg once daily, increased gradually up to a maximum of 120 mg once daily [67, 68]. Doxazosin (adults with hypertension): immediate release (Cardura®, USA) 1 mg once daily, up to a maximum of 16 mg/day; modified release (Cardura GITS® in Portugal, Cardura XL® in the USA) 4 mg once daily, up to a maximum of 8 mg/day [69, 70]. Phenoxybenzamine (FDA label in phaeochromocytoma): 10 mg twice daily, increased on alternate days, usually up to 20–40 mg two to three times daily; the label does not recommend long-term use [71]. Nitroglycerin 2% ointment (Nitro-Bid®, USA; label in angina): 7.5 mg (1.3 cm of ointment) on rising and 6 hours later, with the option of doubling the dose, maintaining a daily nitrate-free interval of 10–12 hours [72]. Gabapentinoids require adjustment to renal function and gradual withdrawal, and vasodilators are titrated against blood pressure [62, 63, 69].

Intralesional botulinum toxin A was assessed in a randomised, double-blind, placebo-controlled pilot trial at the National Institutes of Health, involving 18 adults with painful leiomyomas at least once weekly and pain intensity of at least 4 out of 10; the dose was 5 units per cm² [73]. There was no significant difference in mean lesional pain (primary outcome), a non-significant trend towards less pain at rest, and significant improvement in skin-related quality of life on the Dermatology Life Quality Index, without serious adverse effects [73]. This use is experimental and off-label.

7.3 Uterine leiomyomas

Fibroids should be assessed by a gynaecologist, and most women with the syndrome require medical or surgical intervention earlier than women without a variant [1]. The medical options mentioned are gonadotrophin-releasing hormone agonists and progestogen-releasing intrauterine devices; surgical options are myomectomy and hysterectomy, always with careful histological examination to distinguish atypical smooth muscle neoplasia from leiomyosarcoma [1]. In the absence of a syndrome-specific schedule, the label doses for uterine fibroids apply: leuprorelin acetate (Lupron Depot® 3.75 mg, USA), one intramuscular injection per month for up to 3 months, combined with iron, for preoperative haematological improvement of anaemia caused by fibroids [74]; triptorelin (Decapeptyl® 3.75 mg, Portugal), one intramuscular injection every 4 weeks, started within the first 5 days of the cycle, in principle for no more than 3 months and without a second course of GnRH analogue [75]. The 52 mg levonorgestrel intrauterine system (Mirena®) releases approximately 21 µg/day after 24 days and has a labelled indication in idiopathic menorrhagia (Portuguese SmPC) and heavy menstrual bleeding (FDA), with replacement after 5 years in this indication; it has no labelled indication for fibroids, and its use in that context is off-label [76, 77]. The choice between options follows general gynaecological practice. Early referral for reproductive counselling is recommended, because surgery frequently occurs during reproductive years (section 8) [1].

7.4 Localised renal tumours

The approach to FH-deficient RCC is the most marked exception to the rules applied in other hereditary RCC syndromes. In von Hippel-Lindau disease, hereditary papillary RCC and Birt-Hogg-Dubé syndrome, surgery is recommended when the largest tumour exceeds 3 cm, but in HLRCC metastases occur with small primary tumours, so active surveillance is not recommended [10, 53]. Current sources agree on the following points:

The 2026 EAU guidelines, which recommend nephron-sparing approaches in most hereditary syndromes, explicitly exclude FH-deficient RCC and high-grade tumours in SDH syndromes, for which they recommend immediate surgical intervention [14]. The HLRCC Alliance commentary recalls that, even after early nephrectomy, the risk of distant metastases and predisposition to primary tumours in the contralateral kidney persist [11]. The 2026 Dutch cohort illustrates the problem: in a 56-year-old man under six-monthly surveillance, a 19 mm lesion detected by MRI proved to be a 25 mm RCC with perirenal fat invasion (pT3a) and recurred locally with adrenal metastasis within nine months, despite radical nephrectomy with negative margins [78].

Metastasectomy was assessed in a retrospective series of 23 patients with metastatic HLRCC-associated (17) or SDH-deficient (6) RCC treated at the National Cancer Institute between 2002 and 2024; median systemic therapy-free survival after first metastasectomy was 2.58 years and overall survival 8.17 years, with 72%, 53% and 40% alive at 3, 5 and 10 years [79]. The authors emphasise patient selection and multidisciplinary decision-making, and the retrospective, selected nature of the series precludes comparisons with other strategies [79].

7.5 Carrier surveillance

The 2021 NCCN guideline version adds that, if a relative has an early diagnosis of hereditary RCC, screening should begin 10 years before that relative's diagnostic age, regardless of syndrome [18]. The version current on the NCCN website in October 2026 is 1.2027 and GeneReviews cites version 3.2025; the text of these versions was not accessible for this article (access restricted to registered users), so the NCCN recommendations presented here are those in the 2020 and 2022 publications in the Journal of the National Comprehensive Cancer Network and those cited by GeneReviews [1, 18, 80, 81].

The contrast divergence reflects two concerns: gadolinium is partly retained in the body, without known adverse effects in people with normal renal function, and characterisation of complex cysts benefits from contrast [1, 13]. The age divergence reflects the balance between a risk before 20 years estimated at 1–2% by the 2014 consensus and 2% by age 20 by AACR, and the burden of surveillance in children [10, 13]. A British cost-effectiveness model concluded that annual contrast-enhanced MRI is cost-effective at all modelled starting ages (11, 18, 40 and 60 years), with a mean discounted additional cost of 2,185 pounds per patient in the 11-year cohort and savings in the 40-year cohort [82]. AACR reports the same analysis as cost-effective when starting at 8 years, an age not included in the model's published abstract [13, 82]. The British cohort of 185 individuals documented 187 surveillance examinations in 81 people, detecting three stage 1 RCCs [41]. AACR reports that surveillance proved sensitive and specific, without interval cancers or additional findings requiring invasive investigation [13]. The Hoffman cohort, with negligible cumulative risk before 25 years, led the authors to advocate adult surveillance and consider that the need for paediatric surveillance warrants further study [83]; this is the position of cohort authors, not a society recommendation.

GeneReviews and AACR also recommend renal surveillance in carriers of PCC/PGL-associated variants, although benefit in this group is uncertain [1, 13]. Conversely, heterozygotes for variants associated only with recessive deficiency, such as p.Lys477dup, have not shown increased renal risk [13, 39].

7.6 Systemic treatment of advanced RCC

The 2014 consensus stated that there was no standard therapy and that metastatic disease should preferably be treated in a clinical trial [10]. The rationale for combined blockade of VEGF and epidermal growth factor receptor (EGFR) was the presumed role of FH deficiency in HIF stabilisation and glucose transport dependence [10, 31].

Response values from these studies cannot be ranked against each other. These are single-arm trials or small subgroups, with different populations (in the bevacizumab and erlotinib trial, a germline pathogenic or likely pathogenic FH variant in all 41 tested patients (of 43 enrolled); pathology-defined FH-deficient RCC, germline or somatic, in the Chinese trials), different treatment lines and distinct follow-up periods [15, 17, 85]. The 95% response with tislelizumab and lenvatinib derives from 20 patients at a single centre and has not yet been peer-reviewed. The SUNNIFORECAST analysis shows trends with confidence intervals including no effect. In a Chinese series of 25 tumours, patients treated with checkpoint blockade-based regimens had median PFS of 13.3 months versus 5.1 months with antiangiogenic monotherapy, a non-randomised retrospective comparison [34]. The 2026 EAU guidelines state that, in one trial, immunotherapy combinations with a tyrosine kinase inhibitor had a favourable response compared with bevacizumab and erlotinib, and cite a response rate of 51% for the latter, differing from the 72% published in the final NCT01130519 trial article [14, 15]. The 2022 NCCN guideline version, based on a conference abstract involving 42 patients, cited a 64% response and PFS of 21.1 months [81]; the difference between 64% and 72% results from the transition from the interim abstract to the final publication with 43 patients and confirmed responses.

The societies' positions are as follows. ESMO (2024) states that bevacizumab and erlotinib may be used in advanced FH-deficient RCC [III, B; no EMA or FDA approval] and that recommendations cannot be made for subsequent lines after first-line treatment [16]. NCCN classified bevacizumab and erlotinib as a category 2A option “useful in certain circumstances” for selected patients with non-clear cell RCC of papillary histology, including HLRCC [81], and the 2021 hereditary RCC section included the regimen for metastatic HLRCC-associated RCC, emphasising that inclusion does not constitute an official recommendation and that the regimen is not FDA-approved in this population [18]. GeneReviews describes bevacizumab and erlotinib as beneficial and cabozantinib with nivolumab as potentially useful [1]. EAU lists bevacizumab, erlotinib and immunotherapy in metastatic disease [14].

7.7 Medicines: labels, doses and adverse effects

For checkpoint inhibitors, labelled advanced RCC indications do not exclude the FH-deficient subtype, but the supporting trials were not designed for this subtype; application to children and adolescents with FH-deficient RCC falls outside labelled ages, unless the text provides for it. Initial authorisation dates correspond to the medicine's first approval and not the dates of RCC indication extensions. Regarding the medicines in the Chinese trials, tislelizumab (Tevimbra®) has been authorised in the EU since 15/09/2023 and has an FDA label, both without a renal indication; sintilimab is absent from the EMA medicines database and has no label in the openFDA database; axitinib (Inlyta®, EU since 03/09/2012) and lenvatinib (Kisplyx®, EU since 25/08/2016) have advanced RCC indications in the European label, but not in combination with sintilimab or tislelizumab, which are therefore investigational [89, 96].

The most common bevacizumab- and erlotinib-related adverse effects in the phase 2 trial were acneiform rash (93%), diarrhoea (89%) and proteinuria (78%); the most frequent grade 3 or higher effects were hypertension (34%) and proteinuria (17%), and 52% of the 83 patients had at least one related grade 3 or higher adverse effect. Erlotinib was dose-reduced in 29% of patients (only delays, not reductions, were permitted for bevacizumab); bevacizumab was permanently discontinued in three patients (two acute coronary syndromes and one bronchopulmonary haemorrhage), and two deaths occurred during the study, one from rapid progression and the other from upper gastrointestinal haemorrhage [15]. Management follows the labels:

Withholding bevacizumab before surgery has practical relevance in a syndrome in which metastasectomy and fibroid surgery are frequent.

7.8 Developments in the past 6–12 months and ongoing research

The evidence hierarchy differs for each development and should be read accordingly:

None of these developments represents an authorisation application, Committee for Medicinal Products for Human Use (CHMP) opinion or regulatory decision for the syndrome in the sources consulted.

8. Reproductive Options and Family Counselling

8.1 Risks to relatives

The syndrome is autosomal dominant. Some probands inherited the variant from a heterozygous parent, who may or may not have manifestations; others have a de novo variant, in an unknown proportion [1]. When the proband appears to be the only affected individual, parental testing is recommended: an apparently isolated case may reflect unrecognised manifestations in relatives, reduced penetrance, early parental death or late onset, and de novo occurrence is confirmed only when neither parent has the variant [1]. If the variant is not found in either parent's leucocyte DNA, with biological parentage confirmed, a de novo variant in the proband or parental gonadal (or somatic and gonadal) mosaicism should be considered; sibling recurrence risk is then estimated at 1% [1].

8.2 Predictive testing and age

Testing at-risk relatives for the familial variant enables early identification of those benefiting from surveillance and avoids costly examinations in those who did not inherit the variant [1]. Surveillance may be offered to untested relatives or while results are pending, but definitive testing should take place as early as possible [1]. Age recommendations diverge: the 2014 consensus proposed considering testing from 8–10 years with an individual decision, recalling that in late-onset cancer disorders testing is usually performed from 16–18 years and that an exception is justified when the result implies preventive measures in childhood [10]; GeneReviews suggests testing around the age surveillance begins, which AACR sets at 10 years [1, 13]. Recommendation 10 of ERN GENTURIS 2026 applies directly: at-risk children should receive counselling about predictive testing and family planning on reaching adulthood, or earlier if they wish or if the condition has childhood manifestations [19].

8.3 Reproductive counselling

The ideal time to determine genetic risk and discuss prenatal diagnosis and preimplantation genetic testing is before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. Once the familial variant is identified, prenatal diagnosis and preimplantation genetic testing are possible; views on these options may differ between professionals and within families [1]. The 2026 ERN GENTURIS guideline for cancer predisposition syndromes, developed from 851 publications and consensus among experts and patient representatives, formulated 16 recommendations applicable to FH tumour syndrome [19]:

The guideline emphasises that prenatal diagnosis and PGT reveal only the presence of the variant and do not predict the clinical picture or prognosis, particularly relevant in a syndrome with uncertain renal penetrance and no genotype–phenotype correlation for renal risk [10, 19].

Two specific topics complete counselling. The first is female fertility: fibroid surgery at a young age is frequent, and sources recommend early referral for reproductive counselling and family planning [1]; in the Chinese series of hereditary FH-deficient fibroids, infertility was reported in 54.1%, versus 26.4% of somatic cases [60]. The second is partner testing: GeneReviews recommends genetic counselling and testing of carriers' reproductive partners, because some variants, even without HLRCC manifestations in heterozygotes, can cause fumarate hydratase deficiency when biallelic; if both members of the couple are heterozygous, each pregnancy has a 25% probability of a child affected by the recessive form [1, 28]. In recessive deficiency, heterozygote detection requires prior identification of familial variants, because enzymatic activity in heterozygotes overlaps the normal range [28].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Carrier frequency and penetrance

The prevalence of the clinically manifest syndrome is unknown; Orphanet records more than 200 families described [2]. Carrier estimates derive from genomic databases and vary with pathogenicity criteria: 1/2 563 to 1/3 247 from BRAVO and gnomAD, and 1/901 to 1/1 252 from ExAC and the 1000 Genomes Project [1, 9, 50]. Using broader criteria, Shuch and colleagues estimated that approximately 1 in 1,000 people is a carrier and that lifetime renal cancer penetrance would be 1.7–5.8% [9]. These values measure allele frequencies in databases that are not population cohorts and do not equate to disease prevalence [3, 9]. GeneGuidance records 39 per 100,000 as the upper value of heterozygote frequency, emphasising that this is not the prevalence of manifest disease [3]. Recessive deficiency is much rarer: Orphanet classifies its prevalence as below 1/1 000,000 [3].

Renal risk estimates depend on ascertainment, and the following table shows their range:

In the Kaiser Permanente cohort, among 279 carriers of pathogenic variants, 164 had recessive-form variants (without HLRCC risk), with less ethnic diversity because of a common variant in northern Europeans (c.1431_1433dup); one-third of HLRCC variant carriers were tested for unrelated oncological indications, almost 75% of these were women with suggestive fibroids, and one-quarter were identified by cascade testing [83]. In the Amsterdam Dutch surveillance cohort (77 carriers, 70.1% women, mean entry age 45.7 years, mean follow-up 6.4 years), only two (2.6%) developed RCC, which the authors attribute to late surveillance initiation, patient transfers to other hospitals, and follow-up size and duration [78]. Absence of events or low incidence during short follow-up does not equate to low lifetime risk.

9.2 Regional data and founder populations

The variants c.1210G>T, c.302G>C and c.905-1G>A were confirmed in VariantValidator on NM_000143.4 [4]; the North American variants published as R190H and R58X, numbered in the cytosolic isoform (43 fewer amino acids), correspond to NM_000143.4:c.698G>A, p.(Arg233His) (ClinVar VCV000016236, pathogenic, with R190H as an alternative designation) and NM_000143.4:c.301C>T, p.(Arg101Ter) (ClinVar VCV000016232, pathogenic, alternative designation R58*), descriptions confirmed in VariantValidator, with coordinates NC_000001.11:g.241508643C>T and NC_000001.11:g.241513680G>A [4, 102]. No epidemiological data from Portugal or Brazil on the syndrome were found in the sources consulted; this absence does not demonstrate that publications do not exist. The European reproductive counselling guideline involved the Portuguese association EVITA — Cancro Hereditário and Unidade Local de Saúde de São João, in Porto [19].

9.3 Reference networks and patient associations

In Europe, the syndrome lies at the intersection of three European Reference Networks (ERNs): ERN GENTURIS (genetic tumour risk syndromes), ERKNet (kidney diseases) and eUROGEN (urogenital diseases), which participated with the HLRCC Alliance in the 2025 document on the WHO classification [11]. GeneReviews lists the HLRCC Foundation (hlrcc.org) and the Kidney Cancer Association [1]; the International Kidney Cancer Coalition participated in the same document [11], and EVITA — Cancro Hereditário represents patients in Portugal in ERN GENTURIS work [19]. The European commentary emphasises the importance of referral to specialist centres for assessment and genetic testing of cases with tumour FH deficiency and morphologically complex cases [11].

10. Illustrative Clinical Case

10.1 Case 1 — cascade diagnosis and 8 mm RCC (Canada, 2026)

A 30-year-old woman was referred to an oncogenodermatology clinic after a first cousin was diagnosed with HLRCC associated with a germline pathogenic FH variant [103]. Examination revealed several firm, painful nodules on her back and arm — well-demarcated reddish-brown papules corresponding to cutaneous piloleiomyomas (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12826678/figure/f1-1980e49/). She reported heavy, irregular menstruation, and pelvic ultrasound showed a small uterine fibroid [103]. Genetic testing confirmed the familial variant, and baseline abdominal MRI showed an 8 mm enhancing lesion in the left kidney, visible on T1-weighted sequences before and after contrast in the nephrographic phase (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC12826678/figure/f2-1980e49/) [103]. She underwent partial nephrectomy, and pathology confirmed an RCC typical of HLRCC; she was disease-free ten months later [103].

The authors use the case to emphasise warning signs — piloleiomyomas, early-onset fibroids, renal cancer or a first-degree relative with one of these signs — and the need for multidisciplinary care, including annual renal MRI from 8–10 years, fertility counselling and cascade testing [103]. They also state, citing an observational study by the same group, that at least one biopsy-confirmed piloleiomyoma has a positive predictive value above 90% for HLRCC and constitutes a major diagnostic criterion [103]. The case shows the complete detection chain — diagnosed relative, skin examination, familial variant testing and baseline MRI — and detection of an 8 mm tumour treated with nephron-sparing surgery. Choosing partial nephrectomy for a very small tumour accords with the possibility of complete excision of small tumours allowed by GeneReviews, although NCCN recommends considering radical nephrectomy [1, 18]. Ten months of follow-up is short for conclusions about oncological outcome.

10.2 Case 2 — metastatic RCC at 18 years (Netherlands, 2012)

In a Dutch family with the missense variant c.1002T>G, p.(Ser334Arg) (confirmed in VariantValidator on NM_000143.4), in which only cutaneous and uterine leiomyomas had previously occurred, the proband was 15 years old when the family was investigated and was not clinically assessed; she was advised to undergo testing around 18 years, in accordance with the Dutch protocol at the time, which provided for renal surveillance from 20 [4, 104]. Three years later, she presented with fatigue, weight loss and cough, cervical lymphadenopathy and a large right abdominal mass; she had small back skin lesions suggestive of leiomyomas, which were not biopsied [104]. CT showed a right renal tumour with extensive cervical, mediastinal, abdominal and retroperitoneal lymphadenopathy and an iliac bone metastasis (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC3297757/figure/Fig3/), and cervical lymph node biopsy showed metastatic carcinoma with papillary architecture and prominent halo-surrounded nucleoli, consistent with type 2 papillary carcinoma (Figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC3297757/figure/Fig4/); the patient carried the familial variant [104]. She received sunitinib, with stable disease after two six-week cycles and progression at five months with pleural effusion, followed by temsirolimus, with progression after eight weekly administrations; she died eight months after diagnosis [104]. The pedigree is in Figure 2 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC3297757/figure/Fig2/).

This case, alongside others diagnosed before 20 years, led the authors to reconsider starting testing and surveillance in childhood [104] and was one of the foundations of the 2014 consensus [10]. The medicines used correspond to options at the time and not current options, and the case should not be read as a treatment recommendation. Read together with the Canadian case, it illustrates the difference between symptomatic presentation with disseminated disease and surveillance detection of an 8 mm tumour.

11. Prognosis and Long-Term Follow-up

Prognosis depends chiefly on RCC and the stage at detection. In the British cohort, mean survival was 80.7 months in stages I–II and 15.8 months in stages III–IV, and median survival for symptomatic RCC was 21 months [1, 41]. In the French series, 82% of RCCs were metastatic at diagnosis or metastasised rapidly, with median survival of 18 months in metastatic disease [42]. Among the 27 patients with RCC described by Gardie and cited in the 2014 consensus, 20 (74%) died of metastatic disease diagnosed following symptoms [10]. Patients with tumours detected when small and treated surgically had a favourable prognosis, without evidence of disease after partial or radical nephrectomy [10]. In advanced RCC, the bevacizumab and erlotinib trial recorded median overall survival of 44.6 months in the HLRCC group [15], a value from trial-treated patients that is not directly comparable with historical series.

Surveillance is lifelong in carriers [1]. GeneReviews emphasises that surveillance recommendations still require prospective validation, preferably through international multicentre collaboration, and the 2014 consensus recommended prospective recording of screening outcomes for audit and research [1, 10]. The sources do not provide a validated syndrome-specific quality-of-life assessment instrument; the botulinum toxin trial used the Dermatology Life Quality Index and Brief Pain Inventory for leiomyoma pain [73].

12. Summary and Final Considerations

FH tumour predisposition syndrome results from heterozygous loss-of-function variants in the fumarate hydratase gene, with somatic inactivation of the second allele in tumours and accumulation of fumarate, which stabilises HIF, inhibits α-ketoglutarate-dependent dioxygenases, produces a methylator phenotype and succinates proteins [1, 6, 32]. Cutaneous leiomyomas and early-onset, multiple uterine fibroids are the most frequent manifestations and the principal routes into diagnosis; FH-deficient RCC affects a minority of carriers, with estimates ranging from below 10% to approximately 30% depending on ascertainment, but is aggressive, metastasises from small tumours and determines prognosis [1, 41, 83].

Diagnosis is molecular; FH/2SC immunohistochemistry of renal and uterine tumours is a screening tool that does not distinguish germline from somatic origin [1, 11]. Annual renal MRI surveillance from childhood (10 years in the most recent recommendations) and immediate excision of any tumour, without applying the 3 cm rule, are the pillars of management [10, 13]. In advanced RCC, bevacizumab with erlotinib has the most mature prospective evidence and is the regimen cited by ESMO and NCCN guidelines, always off-label; combinations of checkpoint inhibitors with tyrosine kinase inhibitors have shown activity in single-arm phase 2 trials and await confirmation [15–17, 81]. Biallelic fumarate hydratase deficiency is the recessive allelic disorder; some variants are specific to this form and others to PCC/PGL, making variant interpretation decisive for counselling, partner testing and surveillance [1, 37, 38].

13. References

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