Clinical implications of the family history in patients with lung cancer: a systematic review of the literature and a new cross-sectional/prospective study design (FAHIC: lung)

Compared to other malignancies, few studies have investigated the role of family history of cancer (FHC) in patients with lung cancer, yielding largely heterogeneous results. We performed a systematic literature review in accordance with PRISMA guidelines, searching the PubMed and Scopus databases from their inception to November 25, 2023, to identify studies reporting on the role of FHC in patients with lung cancer. A total of 53 articles were included, most with a retrospective design and encompassing a variety of geographical areas and ethnicities. Thirty studies (56.6%) assessed patients with non-small cell lung cancer (NSCLC), while 17 studies (32.1%) assessed patients with mixed histologies. Overall, the rates of FHC ranged from 8.3 to 68.9%, and the rates of family history of lung cancer ranged from 2 to 46.8%. Twenty-seven studies investigated FHC as a potential risk factor for lung cancer, with more than half reporting an increased risk for subjects with FHC. Five studies reported on the potential role of FHC in determining clinical outcomes, and twelve studies examined the relationship between FHC and germline mutations. Notably, only one study reported a significantly increased rate of germline mutations, including ATM, BRCA2, and TP53, for patients with a family history of lung cancer compared to those without, but both groups had a low prevalence of mutations (< 1%). The FAHIC—Lung (NCT06196424) is the first cross-sectional/prospective study specifically developed to identify FHC patterns and within-family clusters of other risk factors, including smoking, to guide patients with NSCLC to systematic genetic counseling. Acknowledging the largely heterogeneous results of our systematic review and considering the clinical implications of detecting pathogenic germline variants (PGVs), the FAHIC-lung study aims to identify patients potentially enriched with PGVs/likely PGVs to direct them to germline screening outside of the research setting. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-024-05538-4.


Introduction
Familial aggregation and inherited predisposition have been increasingly investigated in multiple cancer types.In breast, ovarian, prostate, and colorectal malignancies, international guidelines recommend genetic counselling in patients showing risk criteria for syndromes of inherited susceptibility to cancer, as aggregations with other malignancies have been widely described within families of these patient populations [1][2][3].
With a predicted number of death of about 160 000 cases in 2023 in Europe and 127 070 in US [4,5], Non-Small Cell Lung Cancer (NSCLC) still remains a leading cause of cancer death worldwide.A positive smoking history represents the main risk factor [6], while environmental factors such as exposure to radon, asbestosis and air pollution have been linked to lung cancer among never smokers [7][8][9].
Few studies have investigated the impact of a positive family history of cancer (FHC) in patients with NSCLC, describing the malignancies that can occur among relatives of patients with NSCLC, while only few and rare genetic syndromes associated with inherited germline genetic mutations, such as the Li-Fraumeni, have been directly linked to lung cancer risk [10].Most of the studies did not provide information on the potential within-family clusters of other risk factors, including exposure to tobacco smoking, environmental carcinogens, and other geographical/epidemiological factors.Additionally, retrospective approaches to this topic are heavily impacted by recall bias and misclassification [11,12].
To underline the importance and potential clinical implications of investigating family history of cancer (FHC) in patients with non-small cell lung cancer (NSCLC), a recent retrospective study conducted in a cohort of 7.788 patients with NSCLC, who underwent commercially available germline genetic testing and reported an FHC of 71%, found that pathogenic germline variants (PGVs) or likely PGVs were present in 14.9% of the cases.Additionally, 2.9% of the cases carried a single PGV in a gene associated with autosomal recessive inheritance.Among positive patients, 61.3% carried a PGV/likely PGV in DNA damage and response (DDR) genes, and 95.1% of them harbored a PGV in genes with potential clinical implications, including BRCA2 (2.8%), CHEK2 (2.1%), ATM (1.9%), TP53 (1.3%), BRCA1 (1.2%), and EGFR (1.0%) [13].
In this manuscript, we present the results of a systematic review of the available evidence on the role of FHC in patients with lung cancer, and the design of the FAHIClung study (NCT06196424), a cross-sectional study that aims to prospectively describe the FHC and the potential within-family distribution of smoking and other risk factors, to identify patients more likely to be carriers of PGVs or likely PGVs.

Literature search strategy and study selection criteria
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.We searched the PubMed and Scopus databases from their inception date to November 25, 2023, to identify potentially relevant articles.The search terms were "non-small cell lung cancer or NSCLC, " "family history, " "lung cancer, " and "risk." The inclusion criteria for the study selection were as follows: (1) patients diagnosed with NSCLC of any stage; (2) available information on the family history of cancer for the included population (e.g., prevalence and type of family history).The exclusion criteria were as follows: (1) lack of information on the family history of cancer; (2) studies not published in English; and (3) case reports.
As this study was a systematic review, ethical approval and informed consent were not required.The study protocol was registered in PROSPERO, an international prospective register of systematic reviews funded by the National Institute for Health Research (NIHR), with the registration code CRD4202450742 (available at: https:// www.crd.york.ac.uk/ prosp ero/ displ ay_ record.php?ID= CRD42 02450 7422).

Data extraction and data synthesis
Two authors (F.C. and K.T.) performed the literature search and evaluated the eligibility of studies using the PICO (patients, interventions, comparison, and outcome) framework following the PRISMA criteria.Assuming a certain heterogeneity in the results, we adopted a textual narrative synthesis approach to summarize the included publications [14].In view of that, we did not establish specific criteria for data synthesis (e.g., the minimum number of studies or level of consistency required for synthesis).
F.C. and T.K. independently reviewed and extracted data from the published papers, including first author, journal name, and year of publication.The prevalence (as a rate) of family history of cancer was summarized in a master table, along with the type of family history collected (e.g., lung-cancer specific vs. family history of any malignancy), study design, study population characteristics, smoking status of study participants and screened relatives (if available), primary tumor type (e.g., NSCLC, small cell lung cancer [SCLC], or others), number of patients included, and disease stage (e.g., early stage vs. advanced stage, if available).Study characteristics, context, and findings were summarized, and similarities/ differences across studies were described in detail.Disagreements between the two authors (F.C. and K.T.) were discussed and resolved with a third independent author (A.C.).

Systematic review-results
We identified a total of 198 potentially relevant articles from the PubMed and Scopus online databases through an initial search strategy.After excluding 41 duplicate articles, we screened and reviewed the titles and abstracts of 157 articles, resulting in 54 being assessed for eligibility.Finally, a total of 53 articles were included in this systematic review.The flow diagram of the study selection process is shown in Fig. 1 while the whole search strategy with publications assessed at each step (identification, screening, eligibility and inclusion) is available as supplementary material (search strategy).
Overall, the vast majority of the studies had a retrospective design, with most of them being case-control or observational retrospective studies, with only one cross-sectional study [15] and one prospective study [16].
Study populations encompassed a variety of geographical areas/ethnicities, with 23 studies (43.4%) enrolling Asian patients, 13 studies (24.5%) enrolling patients with multiple ethnicities (all with a majority of white patients), 11 studies (20.7%) including non-specified ethnicities, and six studies (11.3%) including other populations.Even the included histology types showed heterogeneity, with 30 studies (56.6%) assessing patients with NSCLC, 17 studies (32.1%) assessing patients with a mixed type of lung cancer including small cell lung cancer (SCLC), four studies (7.5%) assessing other/unspecified types of lung cancer, one study (1.9%) assessing patients with adenocarcinoma, and one study (1.9%) assessing patients with EGFR-positive adenocarcinoma only.
FHC was collected through questionnaires in only three studies [17][18][19], while none of them used ad-hoc questionnaires specifically developed to collect FHC and the within-family distribution of other risk factors, including smoking.Twenty-five studies (47.2%) assessed family history (FH) by collecting all malignancies reported among relatives, 21 studies (39.6%) assessed FH of lung cancer,

Eligibility
Fig. 1 Flow diagram of the studies selection process according to the PRISMA guidelines three studies (5.7%) assessed FHC and FH of lung cancer separately, three studies (5.7%) assessed FH of smokingrelated and smoking-unrelated cancers, and two studies (3.8%) assessed FH of pre-specified types of cancer.The degree of relatedness ranged from first to second degree, although it was not reported for the majority of the included studies.One study reported on the smoking status among the relatives of study participants [20] and one study included the assessment of environmental factors (coal exposure) among the risk factors for lung cancer [21].
Overall, the rate of FHC in patients with lung cancer ranged from 8.3 [22] to 68.9% [20], while the rates of FH of lung cancer from 2 [23] to 46.8% [21].Some studies enrolled cohorts of patients potentially enriched for FHC, such as 11 studies which assessed female patients only reporting FHC ranging from 7.7 [24] to 59.4% [25] and FH of lung cancer ranging from 6.2 [26] to 28% [27], four studies which specifically assessed never/light smoker patients only, reporting FHC ranging from 29.1 [28] to 68.9 [20], two studies assessing patients with small aggressive NSCLC, one study assessing male patients only, one study assessing smokers specifically, and one study assessing patients aged ≤ 45 years.A synoptic table with organization of results is available as supplementary file 1.
One study reported a more pronounced increased risk for women aged ≤ 45 years and a synergistic effect of smoking and FHC in increasing the risk of lung cancer [29], while another study reported that FH of lung cancer was specifically associated with an increased risk of early on set lung cancer (< 55 years old) [17].One study that failed to demonstrate an association between FHC and lung cancer diagnosis, reported a significant effect for patients in whom at least one relative with cancer was diagnosed < 50 years of age [20], while one study that failed to demonstrate an association between FH of lung cancer and lung cancer risk, reported a significant effect for female patients only [42].
One study confirmed that FH of lung cancer was associated with risk of lung cancer in both the whole study population and among smokers [37], while another study reported that FH of lung cancer was more strongly associated with lung cancer risk in case of first/second degree of relatedness compared to collateral relatives [40].

Studies investigating the potential impact of FHC on clinical outcomes.
Five studies reported on the potential role of FHC in determining clinical outcomes (Table 2) [19,28,[48][49][50][51][52].One study reported no association between FH of lung cancer and outcomes [48], two studies reported a differential effect for FHC and FH of lung cancer [28,49] and one study reported a decreased risk of death for patients with FHC [50].Similarly, one study reported improving outcomes from PD-1 immunotherapy with increasing burden of FHC [52].

Studies investigating associations between FHC and germline mutations.
Overall, 12 studies reported on the potential relationship between FHC and germline mutations (Table 3) [33,36,37,39,44,46,51,[53][54][55][56][57].Two studies did not show an enrichment of the germline mutations/polymorphisms of interest in patients with FHC [53,55], while three studies suggested a potential enrichment [46,54,57], with only one of them specifically reporting an increased rate of germline mutations including ATM, BRCA2 and TP53 for patients with family history of lung cancer compared to those with no FH [46].Two studies reported a significant effect of the germline status in increasing the risk of lung cancer among patients with no FHC [33,36], while in three other studies the effect was independent of FHC [39,44,46].One study showed a synergistic effect in increasing the risk of lung cancer of XRCC3/ XRCC4 variants and FHC [37].Two studies investigated the potential impact of germline polymorphisms on clinical outcomes, one showing an association between hOGG1 single nucleotide polymorphisms and worse survival specifically in patients without FHC [51], the other showing multifaceted effects of germline NOTCH4 polymorphisms depending on the FHC status [56].

Studies investigating associations between FHC and lung cancer somatic features.
Seven studies reported on the potential association between FHC and lung cancer somatic features (Table 4) [15,52,[58][59][60][61][62].Three studies did not confirm significant associations between FHC and somatic microsatellite instability status [58], somatic DDR genes status [52], or KRAS mutational status [59], while 2 studies reported a significant association between FHC and EGFR mutation [60,61].In addition, another study reported an association between FHC and the occurrence of multiple        No association between FH of lung cancer and HER2/neu status -somatic mutations in patients tested for multiple genes [62].

Studies investigating associations between FHC and other lung cancer features.
Nine studies included in this subgroup reported on associations between FHC and other lung cancer features (Table 5) [18,19,21,22,[63][64][65][66][67].One study reported a link between younger age at diagnosis female gender and FHC [63], one study reported an increased prevalence of FH of breast cancer among female patients with lung cancer [64], while another study reported a 10-years increasing trend over time for the prevalence of FHC [22].Importantly, one study reported a significant association between FHC and smoking [19], while another study reported that FH of lung cancer was more frequent among young women, with synergistic effect with smoking and coil exposure in determining the younger age at diagnosis [21].

Study design and objectives
The FAHIC-Lung study (observational, prospective, multicenter study to investigate the family history of cancer in patients with non-small cell lung cancer) is a cross-sectional/prospective, observational, multicenter study.Consecutive patients with histologically diagnosed NSCLC will be enrolled, regardless of their age, TNM stage, smoking status, and other clinicopathologic characteristics.ClinicalTrials.govidentifier: NCT06196424.The primary objective of the study is the identification of FHC patterns and within-family clusters of other risk factors to address patients with NSCLC for systematic genetic counseling for germline next-generation sequencing (NGS) testing to identify PGVs and likely PGVs.Secondary objectives include the description of clinicopathological and oncological characteristics of patients with NSCLC according to FHC patterns.
Patients' family history will be carefully collected by investigators through a dedicated self-reported study questionnaire, which has been developed for the purpose of this study and validated by the genetic expert of the steering committee (F.G.) (Supplementary file 2).Study questionnaire will focus on: (1) family history of cancer; (2) type of tumors/primary tumor sites among relatives with history of cancer; (3) age at diagnosis among relatives with history of cancer; (4) biological sex of relatives with history of cancer; (5) exposure to tobacco smoking and smoking habits among relatives with history of cancer; (6) geographical origin of participants and relatives with history of cancer; (7) personal history of multiple malignancies; (8) potential professional and environmental exposure to carcinogens of participants and relatives with history of cancer; (9) ethnicity of both participants and relatives with history of cancer.
To minimize risks of recalling bias, patients will be followed up for four weeks through two study visits: the first study visit at enrolment and the follow-up study visit.During the first study visit all patient's clinic-pathologic will be collected and study participants will be given the ad-hoc questionnaire, which will be returned to the study personnel at the follow-up study visit (Fig. 2).
The following clinic-pathologic characteristics will be collected: (1) smoking status (active/passive, package/ year, total years of smoking); ( 2 The study plan includes an observational phase and an analytical phase: Observational phase: after collecting participants' questionnaires, we will first reconstruct patients' family trees with additional information on how other potential risk factors, such as smoking history and exposure to professional/environmental carcinogens, segregate within the families with a history of cancer. Analytical phase: once we have identified family clusters of malignancies and risk factors potentially associated with the highest risk of being carriers of germline PGVs or likely PGVs, we will proceed with the collection of blood samples for germline testing in a subgroup of patients.This will enable us to assess and compare the prevalence of PGVs/likely PGVs between patients more likely to be carriers and the control cohort.This approach aims to achieve a robust comparison, minimize systematic referrals to genetic counseling for all NSCLC patients, and optimize NGS testing requests outside the research setting.Considering the validity and comprehensiveness of high-throughput techniques in identifying PGVs/likely PGVs [68], we will assess the germline status of the groups of interest through whole exome sequencing (WES) after DNA extraction from blood samples in a two step analysis.
In the first step, the raw sequencing data (FASTQ files) will undergo bioinformatic processing.Mapping will be performed using a high-throughput aligner to ensure accurate alignment of the sequenced reads to the human genome.Variant calling will then be conducted to identify deviations from the reference genome.Filtering and  annotation of these variants will focus on a pre-specified list of pre-specified genes known to be associated potentially associated with cancer (Supplementary file 3).This curated gene list will be used to prioritize PGVs/likely PGVs variants.Online tools will be utilized for variant prioritization, organizing the genes based on their correlation with lung cancer, thus enabling us to pinpoint the most relevant variants for further investigation.
In the second step, we aim to discover novel variants that may contribute to lung cancer predisposition.This phase involves a more exploratory analysis of the FASTQ data, looking beyond the known pathogenic variants.We will leverage the extensive genealogical data we have collected on the patients' family histories to identify potential new genetic markers.The stored FASTQ files will be re-analyzed to detect previously unreported variants, incorporating bioinformatics tools and techniques for variant discovery.These include advanced algorithms for variant detection and annotation, as well as integrative approaches to assess the potential pathogenicity of novel variants.The integration of genealogical data will enhance our ability to correlate these novel variants with familial patterns of lung cancer, potentially uncovering new genetic predispositions.This comprehensive approach ensures that we maximize the utility of the sequencing data, providing a robust platform for both targeted and discovery-driven genetic analysis.

Statistical plan and sample size
The sample size of patients enrolled has been determined only for the observational phase of the study.This determination focuses on identifying patients who are more likely to be carriers of pathogenic germline variants (PGVs) or likely PGVs.This approach acknowledges the lack of information on the prevalence of germline PGVs/ likely PGVs in patients with NSCLC who are not selected based on family history of cancer (FHC), as well as the limited knowledge regarding the potential characteristics that will define our group of interest.We hypothesized a prevalence of 10% of participants with an especially enriched family history of cancer to be directed to systematic germline testing; assuming a confidence level of  95% with a total width for the confidence interval of 0.1 (precision of ± 5%), the minimum number of subjects needed to properly describe the group of interest, following a binomial "exact" calculation of the sample size, is 175.To account for potential dropouts, we will enroll a minimum of 180 patients.Descriptive statistics will be used as appropriate to report FHC data, the distribution of within-family other risk factors, and baseline clinicopathologic characteristics.Analyses will be performed using R-Studio software (R Core Team, 2021), and MedCalc ® Statistical Software version 20 (MedCalc Software Ltd, Ostend, Belgium; https:// www.medca lc.org; 2021).

Discussion
To the best of our knowledge, this is the first systematic review summarizing the available evidence on the role of FHC in patients with lung cancer, and the FAHIC-lung study (NCT06196424) is the first cross-sectional/prospective study specifically designed to identify patients with NSCLC more likely to be carrier of PGVs/likely PGVs, that should be systematically referred to genetic counselling and germline testing.
Our review shows that few studies have focused on the family history of cancer (FHC) in patients with lung cancer, resulting in overall heterogeneous results, beginning with the extremely wide range of FHC and family history of lung cancer rates.The category with the highest number of reports included studies assessing FHC as a potential risk factor for developing lung cancer.However, even in this category, the results were largely discordant, with a variety of different approaches and categorizations.Most of the included studies followed a retrospective approach, which is inherently associated with recall bias in collecting family history information, and none used questionnaires specifically designed to collect FHC.To mitigate this bias, we developed our ad-hoc study questionnaire, while the cross-sectional/prospective approach with the 4-week interval will allow study participants to gather and report FHC information as carefully as possible.
Something that set lung cancer apart from other malignancies, where the FHC has an established role in defining the probability of being a carrier of PGVs/likely PGVs, such as ovarian, breast, prostate, and colorectal cancer, is the role of smoking.As mentioned, smoking history represents the main risk factor for lung cancer [6], several evidence shows that passive smoking from family members can be a detrimental factor and that even the smoking habit can be "inherited", with a sort of intergenerational transmission [69,70].The FAHIClung questionnaire will allow us to mitigate this potential bias as well, collecting smoking habit information and environmental exposure to carcinogens among patients' relatives with cancer.
More than a half of the studies that assessed FHC and FH of lung cancer as a potential risk factor for lung cancer concluded that FHC plays a detrimental role, with a potential synergistic effect with smoking, that seems even more pronounced among young/female patients.Our systematic review also suggests that younger patients, female, Asian, and never/light smokers may be especially enriched in FHC, although with no clear/conclusive results, while no somatic genomic feature seems to be significantly associated with FHC, except for EGFR mutations.
Recently, increasing attention has been focused on the study of germline mutations as risk factor for lung cancer, highlighting how DDR genes alterations can be found among patients with lung adenocarcinoma, even in the context of wider within-family primary tumors spectrums, including breast/pancreatic cancers or hematological malignancies [10].Even in the context of TP53associated genetic susceptibility, FHC is gaining a clearer role, to the point of recommending genetic counselling for patients with lung adenocarcinoma younger than 46 years old and with an especially enriched FHC or personal history of multiple primary tumors [71].
Importantly, in our systematic review only one of the studies that investigated the multifaceted role of germline mutations reported a significant enrichment among patients with FHC [46].Rifkin and colleagues first reported a systematic review on the evidence linking germline mutations with lung cancer risk, then validated through a large case-control study of patients undergoing germline whole exome sequencing (WES) the significant association between lung cancer risk and ATM, BRCA2 and TP53 pathogenetic/likely pathogenetic germline mutations [46].However, despite the overall enrichment among controls, variant-based and gene-based analyses showed a low prevalence of germline PGV/likely PGV in both cases and controls [46].In addition, they reported a higher rate of carriers among study participants with FH of lung cancer compared to those without, but with a very low overall prevalence (0.8% vs 0.7% for the combination of ATM/BRCA2/TP53) [46], suggesting that a simplified collection of FHC information is not enough to identify patients with the highest probability of being carriers and to properly optimize germ-line NGC access.
Among gene-specific susceptibility for lung cancer, EGFR-associated one needs a special mention.Genetic counselling is already recommended for patients with somatic EGFR positive NSCLC younger than 50 years, regardless of their family history [10], however, a proper syndromic EGFR-associated lung cancer should be suspected in the case of the novo EGFR T790M mutations, especially with a somatic variant allele frequency (VAF) ≥ 35% [10,72], with even more rare EGFR variants, such as V834L and V843I being increasingly recognized [73,74].Lastly, we will have to consider the complexity related to the multifaceted role of multiple primary tumors.Beyond the consisting evidence linking DDR genes mutations to a personal history of multiple malignancies, recent studies reported on the potential role of pleiotropic loci in determining the risk of multiple malignancies [75].
Our study plan has, however, some limitations.First, we will have to rely on patients' ability and willingness to reconstruct their family history, therefore the recall bias will exert a certain effect despite the cross/ sectional prospective approach.In addition, we have no strictly predefined definition of potential family clusters to be analyzed.However, we can anticipate that the identified group of interest will likely include young female patients with adenocarcinoma histology, never or light smokers, patients with EGFR mutations, patients with a history of multiple primary tumors, and patients with a high burden of family history.This high burden of family history is particularly expected to be enriched in non-smoking associated cancers, including lung cancer, and in the DDR-genes associated cancer spectrum, such as breast, ovarian, prostate, melanoma, and pancreatic cancers.To ensure a comprehensive analysis, we also plan to incorporate other factors collected through our detailed questionnaire.These factors include smoking habits of the patients, passive smoking exposure, working exposure to carcinogens, and smoking habits of family members.By evaluating these additional factors, we aim to identify within-family clusters of other risk factors.Specifically, we will focus on selecting patients without a history of passive smoking, identifying patients with a younger age at diagnosis among their relatives with cancer, and considering patients with low working exposure to carcinogens.Despite having these anticipations, we have deliberately chosen to adopt an unbiased approach without pre-established features to define patients for germline tests.Considering the very low prevalence of germline mutations reported so far [46], this strategy allows for a more comprehensive and inclusive analysis, ensuring that we do not overlook any potential associations or risk factors to unravel the complexity of FHC information and identify patients especially enriched in PGVs/likely PGVs.Furthermore, considering that this is an observational study, we decided to adopt a two steps approach, in order to identify patients at risk as a first step.This, to minimize the potential clinical implications for study participants and let their treating physicians refer them to genetic counseling as per their existing clinical practice.Once the group of interest will be identified, we will amend the protocol to collect blood samples and allocate fundings for germline testing.Lastly, we have to consider that the FAIHC lung study is being conducted in Italy, therefore the study population will mostly consist of white/Caucasian patients.Although this will prevent us from gathering broader information on the potential implications of different races, we will be able to focus and obtain reliable results on patients with European ancestry.
In the context of a worldwide progressive implementation of chest computed tomography based screening programs in subject with smoking history [76], and considering the initial evidence of the potential benefit of screening programs among never smokers and other subjects potentially enriched in FHC/PGVs [77], identifying patients with the highest risk of being carrier of PGVs/likely PGVs would be extremely important to develop dedicated preventing measures in non-smoker subjects.Considering the costs of commercially available germline NGS tests and the potential preventive, prognostic, and therapeutic implications of the detection of germline mutations related to familial cancers, we believe that establishing FHC patterns to identify a subgroup of patients especially enriched in PGVs to direct to germline screening outside of the research setting, would be extremely helpful in optimizing resources, spare time and eventually improve patients' outcomes.

Table 1
summary of the included studies reporting on the potential role of FHC as a risk factor for lung

Table 2
summary of the included studies reporting on the potential implication of FHC on clinical outcomes

Table 3
summary of the included studies reporting on the potential association between FHC and germline mutations

Table 4
summary of the included studies reporting on the potential association between FHC and somatic features

Table 5
summary of the included studies reporting on the potential association between FHC and other features