Hereditary Risk and Syndromic Context of ACC

Epidemiology and Risk Context

Hereditary risk and syndromic context of adrenocortical carcinoma (ACC) refers to the inherited cancer-predisposition syndromes and constitutional developmental disorders in which ACC occurs more often than expected by chance. Within ACC care, this topic lies at the intersection of epidemiology, germline genetics, endocrine oncology, and pediatric cancer predisposition. The most consistently established associations are with germline TP53-related syndromes, especially Li-Fraumeni syndrome, and with Beckwith-Wiedemann syndrome (BWS) or related 11p15 imprinting disorders in childhood.¹²³

Hereditary susceptibility is much more prominent in pediatric ACC than in adult disease. In children, ACC is widely regarded as a sentinel tumor for inherited predisposition even when family history is absent, because de novo and mosaic TP53 alterations occur and because overgrowth phenotypes related to 11p15 abnormalities may be subtle.⁴⁵⁶⁷ In adults, most ACC appears sporadic, but retrospective cohorts suggest that a clinically meaningful minority of cases still harbor germline pathogenic variants, particularly at younger ages or in patients with suggestive personal or family cancer histories.⁸⁹¹⁰

The evidence base is constrained by the rarity of ACC and by reliance on retrospective series, tertiary-referral cohorts, founder populations, and case reports. As a result, the literature is more reliable for identifying hereditary contexts that should prompt genetic evaluation than for estimating absolute syndrome-specific ACC risk or proving benefit from ACC-specific surveillance outside the best-established settings.¹¹¹¹² This limitation is especially important for adult ACC and for rarer reported associations such as MEN1, Lynch syndrome, familial adenomatous polyposis (FAP), Carney complex, SDHx-related syndromes, and other isolated familial observations.¹³¹⁴³

Diagnostic and biologic context

Most ACC is not attributable to a recognized hereditary syndrome, but inherited predisposition has disproportionate clinical importance because it may affect diagnosis, genetic counseling, cascade testing, and surveillance for other malignancies.¹⁵¹⁶¹⁷ The principal biologic themes recur across syndromes: genomic instability and defective tumor suppression through TP53, growth dysregulation and imprinting abnormalities at 11p15, mismatch-repair deficiency, Wnt-pathway activation, and endocrine neoplasia syndromes with recurrent adrenal cortical involvement.¹⁸¹⁹²⁰²¹

What is reliable is the broad principle that pediatric ACC and selected adult presentations warrant hereditary assessment. What is less reliable is any single estimate of the proportion of all ACC explained by germline risk across ages and populations. Clinically, this supports integrating hereditary evaluation into standard ACC workup rather than restricting testing to patients with classic pedigrees alone.⁹¹⁴¹⁰

Contemporary adrenal germline panels may include genes with varying levels of ACC relevance, reflecting overlap between inherited adrenal disease and broader tumor-predisposition biology. However, inclusion of a gene on a panel does not by itself establish a clinically meaningful ACC syndrome, and panel findings still require syndrome-specific interpretation.²²

Major hereditary syndromic settings

TP53-associated cancer predisposition is the dominant hereditary setting for ACC. ACC is a core tumor within the Li-Fraumeni spectrum, and in childhood it may be the presenting malignancy that leads to recognition of the syndrome.²³⁴²⁴²⁵ Across pediatric series, germline TP53 pathogenic variants are frequent, including in children without a classic family history, which has led to the view that childhood ACC itself strongly justifies TP53-focused evaluation.²⁶²⁷⁵²⁸

In adults, TP53-associated ACC is less common but remains clinically relevant, particularly in younger patients and in those with multiple primaries or suggestive family histories. Cohort data indicate that age and family history alone do not identify all carriers, supporting a relatively low threshold for germline TP53 testing in ACC more broadly.⁸⁹²⁹¹⁷ The Brazilian founder variant p.R337H is a notable regional example, producing marked childhood ACC clustering in southern Brazil, but penetrance is incomplete and its epidemiology should not be generalized to all TP53-associated disease.³⁰³¹³²³³

This is the most robust hereditary ACC association in the literature. The practical implication is that ACC, especially in childhood, should strongly prompt TP53-directed counseling, confirmatory germline testing, and syndrome-based surveillance planning for patients and relatives.³⁴³⁵³⁶

BWS, isolated hemihyperplasia, and related 11p15 imprinting abnormalities represent the second major established hereditary context for ACC, again predominantly in childhood.³⁷³⁸³⁹⁴⁰ In this setting, ACC belongs to a broader embryonal tumor predisposition phenotype associated with constitutional dysregulation of growth-promoting pathways, especially IGF2-related signaling and imprinting defects at 11p15.⁴¹¹⁸⁴²

Risk appears concentrated in early childhood and declines substantially with age, distinguishing this syndrome group from the more typical adult pathways of adrenal incidental detection.⁴³⁴⁴ Available data also suggest heterogeneity by molecular subtype within the BWS spectrum, but genotype-specific risk estimates remain limited and are derived largely from observational experience rather than population-based datasets.⁴⁵⁴⁰

This association is well established for pediatric risk stratification but not for adult ACC. Clinically, historical or physical evidence of overgrowth, hemihyperplasia, or related imprinting disorders should prompt consideration of 11p15-directed evaluation in children with adrenocortical tumors.⁴⁶⁴⁷¹⁹

As the narrative moves from these two high-confidence pediatric settings to adult-associated syndromes, the quality of evidence generally decreases and the distinction between frequent adrenal lesions and true ACC predisposition becomes more important.

MEN1 is associated with frequent adrenal cortical abnormalities, but most lesions are hyperplasia or adenomas rather than carcinoma.⁴⁸⁴⁹⁵⁰ ACC is therefore best viewed as a rare manifestation within a syndrome characterized mainly by nonmalignant adrenal findings, rather than as a major ACC-predisposition syndrome.⁵¹⁵²⁵³ Older reports mainly reinforce this broader pattern of nonspecific adrenal cortical involvement rather than materially strengthening the association with ACC itself.⁵⁴⁵⁵

The evidence is moderately consistent but largely retrospective and vulnerable to referral bias. The practical implication is careful follow-up of MEN1-associated adrenal lesions—especially enlarging, functional, bilateral, or otherwise atypical masses—rather than syndrome-wide ACC screening based on current data.⁵⁶⁵⁷⁵⁸

Lynch syndrome, FAP, Carney complex, and other rarer associations

Lynch syndrome has emerging support as an ACC predisposition context, with several cohorts and case reports identifying mismatch-repair pathogenic variants, most often in MSH2 or MSH6, in a small minority of ACC patients.⁵⁹⁶⁰⁶¹⁶² Tumor immunohistochemistry and mismatch-repair-focused assessment may therefore be informative in ACC patients with personal or family histories suggestive of Lynch syndrome. However, absolute ACC risk remains uncertain, and current evidence does not support routine adrenal surveillance for all Lynch carriers.⁶³⁶⁴⁶⁵

FAP has a longstanding but limited literature linking APC-associated disease to adrenal cortical tumors, with molecular findings supporting biologic plausibility through Wnt-pathway dysregulation. Even so, most reported adrenal lesions in FAP are not ACC, and much of the association remains case based.⁶⁶⁶⁷²⁰⁶⁸ Carney complex is more firmly linked to primary pigmented nodular adrenocortical disease than to carcinoma, with ACC reported only rarely in isolated families or case reports.⁶⁹⁷⁰⁷¹⁷²

Additional reported associations, including NF1, SDHx-related syndromes, BRCA2, Werner syndrome, and Birt-Hogg-Dubé syndrome, remain plausible but unestablished as routine clinical ACC-predisposition categories.⁷³⁷⁴⁷⁵⁷⁶⁷⁷⁷⁸⁷⁹ These reports are useful mainly as signals for hypothesis generation and for syndrome recognition in unusual clinical contexts, not as a basis for broad screening recommendations. By contrast, hereditary adrenal disorders such as APECED and endocrine syndromes such as MEN2 illustrate that inherited adrenal disease does not necessarily imply adrenocortical carcinoma susceptibility.⁸⁰⁸¹⁸²

What is reliable in this group is the need to consider syndrome-specific clues when ACC occurs alongside characteristic extracortical cancers or endocrine phenotypes. What is not reliable is any strong estimate of ACC penetrance or evidence for routine adrenal screening across these syndromes.¹¹⁸³¹² Reports invoking broader adrenal genetics, such as GNAS-related mosaic disorders, remain indirect and do not currently establish recognized hereditary ACC settings.⁸⁴

Clinical implications, surveillance, and research limits

Taken together, the literature supports the highest yield for hereditary evaluation in pediatric ACC, in younger adults, and in patients with personal or family histories suggestive of TP53-related disease, Lynch syndrome, or another cancer predisposition syndrome.¹⁵⁸⁵¹¹ Recognition of a hereditary syndrome may alter counseling, cascade testing, and surveillance for second primary malignancies more than it changes the local treatment of the index ACC, which still depends primarily on surgery, staging, endocrine assessment, and systemic therapy when indicated.³⁴⁸⁶³⁶

The main limitation of the field is that many syndromic links beyond TP53 and pediatric 11p15 disorders remain supported chiefly by referral cohorts and case reports. This makes causality, penetrance, and surveillance benefit difficult to define, especially in adults and in rare syndromes with broad tumor spectra.¹¹⁴³ For research, hereditary ACC remains a useful model for adrenal tumorigenesis, but progress will likely depend on multicenter registries, more standardized germline testing strategies, and clearer integration of molecular subtype with age-specific clinical risk.⁸⁷²²¹

Included Articles

PMID 1351034: This case report describes adrenocortical carcinoma arising in a patient with familial adenomatous polyposis and identifies loss of the normal APC allele in the tumor. The report supports familial adenomatous polyposis as a hereditary context in which extracolonic adrenal cortical malignancy can occur.⁶⁶

PMID 1352309: In a MEN1 cohort, adrenal enlargement was seen in 37% of patients, usually as stable bilateral hyperplasia or adenoma without hormone excess, while one patient developed feminizing ACC after interval growth from prior small bilateral lesions. The report frames MEN1-associated adrenal cortical lesions as having malignant potential but likely not a primary MEN1 lesion.⁸⁸

PMID 1569604: This article uses childhood adrenocortical carcinoma as a sentinel tumor to identify cancer-prone families and reports novel germ-line p53 mutations in two such families, supporting the association between pediatric ACC and Li-Fraumeni syndrome or related hereditary cancer predisposition.⁸⁹

PMID 1583638: This article identifies Beckwith-Wiedemann syndrome as a hereditary overgrowth syndrome associated with embryonal tumors including adrenocortical carcinoma, and discusses familial transmission linked to 11p15.5 with evidence consistent with genomic imprinting.³⁷

PMID 1675702: This case report and literature review describes adrenal neoplasms occurring in familial adenomatous polyposis, including adrenocortical adenoma and one reported lesion that later recurred as adrenal carcinoma. It frames FAP as a hereditary context in which incidentally detected adrenal tumors may warrant heightened concern for malignancy.⁹⁰

PMID 1910026: A pedigree study of 47 Japanese childhood adrenocortical carcinoma probands found familial clustering of early-onset cancers in several families, including patterns compatible with Li-Fraumeni syndrome. Mothers, particularly for breast cancer, and relatives with liver cancer, osteosarcoma, and lung cancer before age 45 had higher cancer occurrence than the general population.⁹¹

PMID 2012133: This case report and review identifies Wiedemann-Beckwith syndrome as a hereditary overgrowth condition associated with a 5-10% risk of embryonal tumors, including adrenocortical carcinoma. It notes ACC among the more commonly reported WBS-associated neoplasms and emphasizes the need for neoplasia monitoring in affected children.⁴⁶

PMID 2821320: This review of Wiedemann-Beckwith syndrome reports that affected children have an elevated tumor risk, with malignant tumors described mainly as nephroblastomas and adrenocortical carcinomas. It also highlights recurrent constitutional abnormalities involving chromosome 11p15, while noting uncertain causal links and limited value of cytogenetics for identifying those at highest tumor risk.⁹²

PMID 2827818: This breast cancer pedigree study describes the SBLA familial cancer syndrome as including adrenocortical carcinoma among associated tumors, alongside sarcomas, breast cancer, brain tumors, lung and laryngeal cancers, and leukemia. The excerpt therefore contributes hereditary syndrome context relevant to ACC risk.⁹³

PMID 2921038: This article links Beckwith-Wiedemann syndrome with markedly increased childhood adrenocortical carcinoma risk and maps the implicated constitutional duplication to chromosome 11p15.5. It supports hereditary predisposition context for ACC by describing BWS cases with 11p15 duplication and suggesting an ACC susceptibility gene in this region.³⁸

PMID 6249939: This pediatric series describes congenital overgrowth syndromes as ACC risk contexts, reporting associations of hemihypertrophy and Beckwith-Wiedemann syndrome with childhood adrenocortical carcinoma. It presents a child with hemihypertrophy who developed Cushing syndrome from ACC and summarizes prior documented ACC cases in these syndromic settings.³⁹

PMID 6958872: This case report describes adrenocortical carcinoma occurring in children from two Li-Fraumeni syndrome families, alongside breast cancer, rhabdomyosarcoma, and brain tumors. It emphasizes that pediatric ACC is very rare but may be over-represented in familial childhood cancer syndromes, so its occurrence should prompt consideration of hereditary cancer predisposition.⁹⁴

PMID 7491526: In a prospective MEN1 cohort, 40% developed adrenal cortical enlargement during longitudinal follow-up, with most lesions indolent but a minority showing progression, marked atypia, or carcinoma. The report supports MEN1 as a hereditary context in which adrenal cortical lesions warrant surveillance because of malignant potential.⁵⁶

PMID 7621447: This report identifies Beckwith-Wiedemann syndrome as a hereditary overgrowth condition that predisposes children to adrenocortical carcinoma and other embryonal tumors, citing an approximate 12% risk of rare childhood neoplasms. It also links this risk context to chromosome 11p abnormalities and dysregulated IGF-II biology in an associated adrenal tumor.⁴¹

PMID 7712645: This review identifies Beckwith-Wiedemann syndrome as a hereditary cancer-predisposition condition associated with childhood tumors including adrenocortical carcinoma. It notes tumor risk is concentrated in early childhood, with hemihypertrophy linked to higher malignancy risk in affected children.⁴³

PMID 7767487: This family case report links adrenocortical carcinoma to an inherited TP53 germline deletion at codon 236 in a cancer-predisposition syndrome resembling Li-Fraumeni. The affected patient developed an androgen-producing ACC in young adulthood alongside familial clustering of brain tumors and leukemia.⁹⁵

PMID 7966399: In a small pediatric ACC series, germline TP53 mutations were identified in 3 of 6 tested children, including cases without classic Li-Fraumeni family history. The report supports childhood ACC as a strong marker of hereditary cancer predisposition and suggests considering germline TP53 testing and family risk assessment.²⁶

PMID 8034301: This family report links childhood adrenocortical carcinoma to Li-Fraumeni syndrome through a germline TP53 frameshift deletion at codon 215, found in affected relatives with a cluster of early-onset cancers including rhabdomyosarcoma, osteosarcoma, and breast cancer.⁹⁶

PMID 8048849: This article identifies adrenocortical carcinoma as part of the Li-Fraumeni or SBLA hereditary cancer spectrum, describing family pedigrees in which childhood ACC occurred alongside breast cancer, sarcoma, leukemia, brain tumor, and other early-onset malignancies linked to inherited p53 mutations.⁹⁷

PMID 8527048: This case report documents Li-Fraumeni syndrome in a Korean family and notes adrenocortical carcinoma as one of the cancers associated with this autosomal dominant hereditary syndrome. It links the syndrome to a germline TP53 mutation, highlighting inherited cancer predisposition as relevant risk context for ACC.⁹⁸

PMID 8613422: A cooperative cancer research program seminar on Li-Fraumeni syndrome prompted recognition of Japanese pedigrees and study of its occurrence in Japanese families with childhood adrenocortical carcinoma, highlighting hereditary cancer syndrome context for ACC risk.⁹⁹

PMID 8776593: The article links adrenocortical carcinoma to Beckwith-Wiedemann syndrome and chromosome 11p15.5 imprinting biology, noting that ACC is among childhood tumors showing specific loss of maternal 11p15 alleles. It supports hereditary risk context rather than ACC-specific diagnosis or treatment guidance.¹⁸

PMID 8841187: This article links adrenocortical carcinoma to Beckwith-Wiedemann syndrome, describing the syndrome as a cancer-predisposing condition associated with childhood tumors including ACC. It identifies p57KIP2 mutations and imprinting abnormalities at 11p15.5 as part of the syndrome’s genetic basis.⁴²

PMID 8955618: This case report links very early childhood adrenocortical carcinoma to Li-Fraumeni spectrum cancer predisposition through a de novo germline TP53 mutation at codon 248, despite no family history of cancer. The adrenal tumor also showed loss of the wild-type TP53 allele.¹⁰⁰

PMID 9569035: This report describes two early childhood adrenocortical tumors occurring in a Li-Fraumeni syndrome family with a novel germline TP53 exon 5 mutation, reinforcing hereditary cancer predisposition as an important risk context for pediatric adrenocortical tumors.¹⁰¹

PMID 9598730: This pediatric case report links adrenocortical carcinoma to hereditary cancer predisposition by describing a 20-month-old girl with metastatic nonfunctioning ACC and a germline p53 mutation consistent with Li-Fraumeni syndrome. The report reinforces that childhood ACC can occur in the setting of inherited TP53 abnormalities, while the contribution of coexisting Turner syndrome remains uncertain.¹⁰²

PMID 9825943: This case report links pediatric adrenocortical carcinoma to Li-Fraumeni syndrome, describing a 4-year-old boy with premature puberty from ACC in a family carrying a germline TP53 codon 248 mutation. The excerpt also notes that adrenocortical carcinoma is a typical but uncommon Li-Fraumeni tumor type.¹⁰³

PMID 9917751: This case report notes that isolated hemihypertrophy and Beckwith-Wiedemann syndrome are cancer-predisposition contexts in which adrenocortical carcinoma has been reported among the more frequent associated embryonal tumors. The article frames limb asymmetry as a clinical clue warranting attention for underlying malignancy risk.⁴⁷

PMID 10640978: This case report on an extended Li-Fraumeni kindred supports hereditary cancer predisposition as an ACC risk context, listing adrenocortical carcinoma within the Li-Fraumeni tumor spectrum and noting that ACC can occur at very young ages in affected families.¹⁰⁴

PMID 10738297: This review identifies Beckwith-Wiedemann syndrome as a hereditary context associated with childhood adrenocortical carcinoma and links these tumors to abnormalities at chromosome 11p15 and TP53. It also notes that children with Beckwith-Wiedemann syndrome have an overall increased risk of developing tumors, including ACC.¹⁹

PMID 10852426: This case report notes that patients with familial adenomatous polyposis may have an increased prevalence of adrenal lesions, most often nonfunctioning adenomas, while prior reports have also described adrenocortical carcinoma. The excerpt also discusses APC-related loss of heterozygosity as a possible mechanism linking FAP to adrenal neoplasia.⁶⁷

PMID 11498785: In families with germline TP53 mutations consistent with Li-Fraumeni or Li-Fraumeni-like syndromes, adrenocortical carcinoma was strongly associated with carrier status and showed one of the largest excesses versus population rates. The study supports ACC as a characteristic hereditary-syndrome cancer within the TP53 predisposition spectrum.²³

PMID 12200603: This case-based report identifies Li-Fraumeni syndrome with a germline TP53 codon 175 mutation as a hereditary cancer predisposition context that includes adrenocortical carcinoma among its core tumor spectrum, noting ACC is typically seen in young children within affected families.¹⁰⁵

PMID 14963361: This case report describes adrenocortical carcinoma occurring in a woman with Werner syndrome, presented as the first reported association in that hereditary premature-aging disorder. The article frames the concurrence as a possible hereditary cancer-syndrome link but emphasizes that additional cases are needed to determine whether the association is causal or coincidental.⁷³

PMID 15073606: This case report links a de novo germline TP53 exon 10 stop mutation in a Li-Fraumeni syndrome phenotype to a mutational region described in childhood malignant adrenocortical tumor, highlighting hereditary cancer predisposition context relevant to ACC risk assessment.¹⁰⁶

PMID 15132719: In a family with isolated familial somatotropinoma, one affected woman developed a virilizing adrenocortical carcinoma with 11q13 loss of heterozygosity, but the authors interpret the adrenal carcinoma as likely sporadic rather than a recognized feature of the familial pituitary syndrome.¹⁰⁷

PMID 15761519: This review identifies Carney complex as an autosomal dominant familial multiple neoplasia syndrome associated with primary pigmented nodular adrenocortical disease and ACTH-independent Cushing syndrome, highlighting hereditary predisposition and family-based screening considerations relevant to adrenal cortical disease.⁶⁹

PMID 16534790: This case report identifies adrenocortical carcinoma as part of the Li-Fraumeni syndrome tumor spectrum and describes a family in which an 8-year-old relative developed adrenal cortical carcinoma with a confirmed germline TP53 truncating mutation. The report emphasizes hereditary cancer history as a key clue to syndrome recognition.¹⁰⁸

PMID 16786124: A small Polish case-control study found the TP53 codon 72 Pro allele more frequent in adrenocortical carcinoma than in benign adrenocortical tumors or controls, with an estimated threefold increased ACC risk. No association was seen for adenomas, suggesting a possible inherited susceptibility signal rather than a general adrenal tumor risk.¹⁰⁹

PMID 16828412: This review notes Carney complex as a multiple-endocrine-neoplasia-like hereditary syndrome that can include primary pigmented nodular adrenocortical disease, sometimes with Cushing syndrome, alongside other endocrine and nonendocrine tumors.¹¹⁰

PMID 17235589: In a prospective screening cohort of genetically confirmed MEN1 patients, adrenal involvement was detected in 55%, usually as small, benign, nonfunctioning lesions, but rare malignant transformation to adrenocortical carcinoma occurred. The study did not confirm a previously suggested MEN1 genotype-phenotype correlation for adrenal lesions.⁴⁸

PMID 17318340: This family-based report reinforces Li-Fraumeni syndrome as a hereditary context for adrenocortical carcinoma and shows that not all germline TP53 variants found in such families are truly pathogenic. Functional and segregation analyses distinguished a causative TP53 splice-site mutation from an exon 7 variant lacking convincing disease association.¹¹¹

PMID 18328987: In MEN1, primary adrenocortical neoplasms occur in about 20-40% of patients and are typically bilateral, hyperplastic, nonfunctional, and clinically indolent. The review also notes that hyperaldosteronism is rare and pheochromocytoma is uncommon in MEN1.⁴⁹

PMID 18428420: Li-Fraumeni syndrome is described as an autosomal dominant cancer predisposition syndrome that includes adrenocortical carcinoma among its core early-onset tumor spectrum. The article outlines germline TP53 sequencing as a method to confirm Li-Fraumeni or Li-Fraumeni-like syndrome and support screening of at-risk relatives.³⁴

PMID 18786442: This case report identifies adrenocortical carcinoma arising in infancy within a Li-Fraumeni syndrome family carrying a germline TP53 mutation, reinforcing ACC as part of the hereditary cancer spectrum. It also notes that revised Li-Fraumeni diagnostic criteria include any child with adrenocortical carcinoma.¹¹²

PMID 18989156: This pediatric case report links infantile ACC with a germline TP53 mutation and later osteosarcoma, underscoring Li-Fraumeni syndrome as an important hereditary context for childhood ACC. The excerpt notes markedly elevated ACC incidence in LFS families and a high reported prevalence of germline TP53 mutations among children with ACC.²⁷

PMID 19169494: This case report notes that Carney complex can include primary pigmented nodular adrenocortical disease as a major diagnostic feature and discusses overlap with MEN1 phenotypes. It highlights hereditary endocrine neoplasia syndromes as relevant background when evaluating adrenal cortical disease risk context.¹¹³

PMID 19204208: In a clinical germline p53 testing cohort, adrenocortical carcinoma was a strong marker of hereditary cancer predisposition: 14 of 21 patients with childhood ACC had detectable p53 mutations. The study supports ACC as a core Li-Fraumeni–associated tumor and notes that Chompret criteria include ACC at any age regardless of family history.⁴

PMID 19496980: The report identifies Beckwith-Wiedemann syndrome as an overgrowth syndrome associated with increased risk of embryonal tumors including adrenocortical carcinoma, with tumor risk declining with age and approaching baseline after about 10 years.⁴⁴

PMID 19714490: This case report links pediatric adrenocortical carcinoma with germline TP53 tetramerization-domain mutation R342X and reinforces ACC as a characteristic tumor in Li-Fraumeni syndrome or inherited TP53-altered phenotypes. The report also notes that germline TP53 mutations may be especially frequent in children with ACC.¹¹⁴

PMID 19717094: This review highlights the Brazilian founder germline TP53 R337H mutation as an important hereditary risk context for ACC, noting its high prevalence in southern Brazil and its association with childhood adrenocortical carcinoma within the broader Li-Fraumeni spectrum.³⁰

PMID 20017945: This family-based report reinforces Li-Fraumeni syndrome as an inherited risk context for adrenocortical carcinoma, noting that ACC is part of the core tumor spectrum and that Chompret criteria consider ACC sufficient to trigger suspicion of the syndrome regardless of family history.¹¹⁵

PMID 20301390: This GeneReviews summary on Lynch syndrome notes that adrenocortical carcinoma has been reported in affected individuals, but current data are insufficient to show that Lynch syndrome clearly increases ACC risk. It therefore supports a cautious hereditary-risk framing rather than a confirmed association.⁶³

PMID 20421238: This case report describes adult ACC in a 31-year-old woman with a novel germline TP53 p.P177R mutation and a family history suggestive of Li-Fraumeni syndrome, supporting inherited cancer predisposition assessment in selected ACC patients. The authors emphasize the importance of TP53 screening for risk evaluation in ACC with suspected hereditary syndrome.¹¹⁶

PMID 20426520: This case report highlights Li-Fraumeni syndrome as a hereditary risk context for pediatric adrenocortical carcinoma, identifying a familial germline TP53 R337P mutation in a family with childhood ACC and multiple early-onset cancers. It also notes that mutation carriers may warrant targeted surveillance with imaging and endocrine studies, although survival benefit from early detection remains uncertain.¹¹⁷

PMID 20842232: This case report and literature review emphasizes that synchronous ACC with other primary malignancies is exceptionally rare, with only five previously reported cases identified. It also summarizes inherited syndromes linked to increased ACC risk, including Li-Fraumeni, Beckwith-Wiedemann, Gardner syndrome, and MEN1.¹¹⁸

PMID 20978149: This study supports adrenocortical tumors as a manifestation of familial adenomatous polyposis, with biallelic APC inactivation and Wnt/beta-catenin pathway activation identified in FAP-associated adrenal lesions. In contrast, APC and WTX alterations appeared uncommon in sporadic ACC lacking CTNNB1 mutations.²⁰

PMID 21069576: This case report describes adrenocortical carcinoma arising in a patient with multiple endocrine neoplasia type 1 and a novel germline MEN1 mutation, supporting hereditary syndrome context for ACC. The report notes that adrenal lesions in MEN1 are often benign, but MEN1 gene or 11q13 abnormalities may be associated with malignant adrenal cortical neoplasms.¹¹⁹

PMID 21225464: This case report suggests adrenocortical carcinoma may occur as a rare extracolonic manifestation in Lynch syndrome, particularly in an MSH2 mutation carrier. Tumor findings included loss of the normal MSH2 allele and absent MSH2 protein expression, supporting a mismatch-repair–related association despite microsatellite stability.¹²⁰

PMID 21266030: This case report describes functioning bilateral adrenocortical carcinomas in a 31-year-old patient with MEN1 and notes that ACC occurs in a minority of MEN1 patients, while bilateral ACC had not previously been reported in the cited literature. The report highlights MEN1, particularly an exon 2 MEN1 mutation, as a hereditary context warranting attention when adrenal lesions are identified.¹²¹

PMID 21374038: This methods overview notes that germline TP53 mutations in Li-Fraumeni syndrome increase risk of adrenocortical carcinoma. Within the ACC wiki, this supports hereditary risk context by highlighting TP53-associated predisposition rather than ACC-specific tumor testing practice.¹²²

PMID 21415556: This case report notes that adrenal lesions occur in about 30-40% of patients with MEN1 and can include hyperplasia, adenoma, and less commonly adrenocortical carcinoma, with most lesions being hormonally silent. It highlights MEN1 as a hereditary context in which adrenal cortical lesions may arise, although the reported patient had ACTH-independent macronodular adrenal hyperplasia rather than ACC.¹²³

PMID 21916912: In a retrospective MEN1 cohort with Cushing syndrome, two of three patients with ACTH-independent adrenal Cushing syndrome had adrenocortical carcinoma, highlighting MEN1 as a hereditary context in which aggressive adrenocortical tumors can occur. The series also notes prior reports of ACC in MEN1, although numbers were small.⁵⁷

PMID 22112809: This case report describes what the authors identify as the first documented adrenocortical carcinoma arising in a patient with Carney complex, specifically in a background of primary pigmented nodular adrenocortical disease and a germline PRKAR1A frameshift mutation. It suggests Carney complex may represent a rare hereditary context for ACC and may warrant surveillance consideration.⁷⁰

PMID 22170717: In a cohort of 103 adult ACC patients, germline TP53 mutations were uncommon overall but were found in 13% of those diagnosed before age 40, while being rare in older adults. The findings support considering TP53 germline testing in younger adults with ACC and suggest age modifies hereditary risk context.⁸

PMID 22209747: This review summarizes inherited susceptibility to ACC, emphasizing that childhood ACC is commonly associated with hereditary syndromes, especially Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome, while adult associations with MEN1, FAP, NF1, and HNPCC are less well substantiated. It also notes the lack of ACC-specific population-based data and highlights clinical features that should prompt genetic evaluation.¹

PMID 22414215: This case report highlights adult ACC occurring in a patient with germline TP53 mutation consistent with Li-Fraumeni syndrome, identified after evolving family history of early breast cancers. The report emphasizes considering hereditary cancer syndromes in ACC and notes recommendations for TP53 germline testing in younger patients.¹²⁴

PMID 22476103: This review notes that Li-Fraumeni syndrome is a cancer predisposition syndrome relevant to adrenocortical carcinoma and highlights the importance of TP53 genotyping in patients with ACC. It also cites possible survival benefit from comprehensive presymptomatic screening in Li-Fraumeni patients.⁸⁶

PMID 22516243: This review identifies adrenocortical carcinoma as a rarely reported Lynch syndrome-associated tumor, including a new case in a 29-year-old man with a germline MSH2 mutation and loss of MSH2/MSH6 by immunohistochemistry. The excerpt emphasizes that evidence remains insufficient to justify routine ACC surveillance or its inclusion in general Lynch syndrome screening guidelines.⁶⁴

PMID 22796286: In childhood ACC, hereditary predisposition is a key risk context: the review states that any child with adrenocortical carcinoma should undergo constitutional TP53 testing for Li-Fraumeni syndrome, with Beckwith-Wiedemann syndrome also noted as an associated predisposition. It also cites a very low pediatric incidence of about 0.3 cases per 1,000,000.⁵

PMID 23175693: In a prospective unselected ACC clinic cohort, germline TP53 mutations were identified in 7.5% of tested patients and 5.8% of adults, including several diagnosed after age 45. Mutation carriers were not reliably captured by classic Li-Fraumeni clinical criteria or by age and family history alone.⁹

PMID 23299088: This review summarizes sex-related epidemiologic patterns in adrenocortical carcinoma, noting a reported slight female predominance in adults, possible male-specific association with heavy smoking, and possible increased risk with oral contraceptive use in women. It also highlights hereditary syndrome associations and age-related sex differences in pediatric cases.¹²⁵

PMID 23377869: This review emphasizes that ACC, despite an incidence of about 0.72 per million in the United States, is strongly linked to hereditary cancer predisposition, especially Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. It notes that all individuals with ACC should be considered for genetics referral and germline TP53 testing regardless of family history.¹⁵

PMID 23522203: This case report notes that adrenocortical carcinoma is among the tumor types associated with Li-Fraumeni syndrome and Li-Fraumeni-like syndrome, which are linked to germline TP53 mutations and familial clustering of early-onset malignancies.¹²⁶

PMID 23563208: This case-based review identifies Li-Fraumeni syndrome as a hereditary context for ACC, noting germline TP53 mutation and stating that adrenocortical carcinoma is part of the syndrome spectrum and may occur regardless of family history in TP53 testing criteria. It reports that about 3% of Li-Fraumeni patients develop ACC.¹²⁷

PMID 23587008: This hypothesis review identifies Li-Fraumeni syndrome as a hereditary TP53-associated cancer predisposition syndrome in which adrenocortical carcinoma is among the characteristic early-onset malignancies. It frames ACC risk within the broader inherited context of childhood and young-adult cancer susceptibility in LFS.¹²⁸

PMID 23752102: This study supports adrenocortical carcinoma as a Lynch syndrome-associated cancer, finding Lynch syndrome in 3.2% of a prospectively counseled ACC cohort. It recommends genetic risk assessment for patients with ACC who have a personal or family history of Lynch-associated tumors, and suggests tumor immunohistochemistry screening may help identify affected families.⁵⁹

PMID 23869313: This case report highlights adrenocortical carcinoma as a rare manifestation and possible presenting feature of MEN1, with virilization and ACTH-independent Cushing syndrome prompting diagnosis. The excerpt also notes reported adrenal involvement in MEN1 and a low but recognized incidence of ACC in this hereditary syndrome.¹²⁹

PMID 24122735: In Southern Brazilian children with cancer, germline TP53 p.R337H was identified in 3.8% overall and in most mutation-positive cases the tumor was ACC. The study supports ACC as part of Li-Fraumeni or Li-Fraumeni-like hereditary risk, with a notable Brazilian founder mutation context.³¹

PMID 24423978: This review frames ACC as an ultrarare malignancy with incidence around 0.72 to 2 per million per year, female predominance, and diagnosis typically in mid-adulthood, while noting a higher relative incidence in childhood. It also summarizes hereditary risk context, highlighting TP53-associated Li-Fraumeni syndrome, Southern Brazilian p.R337H prevalence, and less common associations including Beckwith-Wiedemann syndrome, MEN1, Lynch syndrome, FAP, neurofibromatosis type 1, and Carney complex.⁸⁷

PMID 24625245: This article notes that the germline TP53 p.R337H founder mutation, linked to Li-Fraumeni syndrome, is identified in more than 90% of Brazilian childhood adrenocortical carcinoma cases and is unusually prevalent in southern and southeastern Brazil. It supports hereditary-risk context for ACC rather than tumor-specific management.³²

PMID 25115713: This review describes the southern Brazil founder TP53 R337H germline variant as a low-penetrance hereditary risk factor strongly associated with childhood adrenocortical carcinoma, helping explain the region’s markedly elevated pediatric ACC incidence. It also places ACC within Li-Fraumeni syndrome, where adrenocortical tumors are a recognized component.¹³⁰

PMID 25226867: This case report highlights Li-Fraumeni syndrome as a hereditary risk context for adrenocortical carcinoma, noting ACC among the most common pediatric tumors in TP53-associated disease. It provides additional evidence that the germline TP53 tetramerization-domain variant p.Arg342Pro is pathogenic within an LFS family.¹³¹

PMID 25905240: This report describes adrenocortical carcinoma arising in a young patient from an Amsterdam II hereditary nonpolyposis colorectal cancer family with an MSH2 mutation, supporting Lynch syndrome as a possible hereditary context for some ACC cases. The ACC showed loss of MSH2 expression despite being microsatellite stable on the standard five-marker panel.¹³²

PMID 26029016: Li-Fraumeni syndrome is presented as a hereditary cancer predisposition syndrome linked to germline TP53 mutations in which adrenocortical carcinoma is a core associated malignancy. The report also notes that TP53 mutations may be de novo, so ACC risk context can exist even without a strong family history.¹³³

PMID 26049273: This review identifies Li-Fraumeni syndrome from germline TP53 mutations as a hereditary context strongly associated with adrenocortical carcinoma, especially in childhood. It also notes the Southern Brazil TP53 R337H variant as particularly linked to ACC and discusses syndrome-specific surveillance efforts.¹³⁴

PMID 26452166: In pediatric patients from Brazil, the germline TP53 p.R337H variant, already linked to adrenocortical tumors, was also identified in 7 of 83 neuroblastoma cases and is discussed as part of a broader Li-Fraumeni-like cancer predisposition context relevant to ACC-associated hereditary risk.¹³⁵

PMID 26521198: This case report notes that familial adenomatous polyposis is an inherited cancer predisposition syndrome with extracolonic manifestations that include adrenocortical tumors. In ACC context, it supports FAP as a hereditary risk condition to consider when assessing patient background and cancer predisposition.¹³⁶

PMID 26660147: This review emphasizes hereditary predisposition in ACC, especially childhood disease, highlighting frequent germline TP53 mutations and associations with Li-Fraumeni and Beckwith-Wiedemann syndromes, while also noting adult ACC links with TP53, Lynch syndrome, MEN1, and less commonly FAP and Carney complex.²

PMID 26833171: This lecture identifies adrenocortical carcinoma as a core Li-Fraumeni syndrome tumor and notes that revised Chompret criteria include ACC irrespective of family history. It also reports that germline TP53 mutations are found in about 55% of children with ACC, with the Brazilian TP53 R337H founder mutation overrepresented in pediatric ACC.²⁴

PMID 27075352: This review emphasizes hereditary risk context for ACC, describing six associated cancer predisposition syndromes and highlighting Li-Fraumeni syndrome as a major association. It notes that inherited TP53 mutations are particularly relevant in pediatric ACC and supports genetic counselling and syndrome-directed testing in affected patients and families.⁸⁵

PMID 27144940: This familial case report supports adrenocortical carcinoma as a Lynch syndrome-associated tumor in adults, identifying intergenerational ACC with a germline MSH2 mutation and concordant loss of MSH2/MSH6 on tumor immunohistochemistry. The report argues that ACC should be considered in Lynch syndrome diagnostic frameworks and surveillance planning.¹³⁷

PMID 27374712: This retrospective Korean Li-Fraumeni syndrome series reinforces germline TP53 mutation as a hereditary risk context for adrenocortical carcinoma, with ACC appearing among the core LFS-associated tumors. The cohort also showed early tumor onset and frequent multiple primary cancers in TP53 mutation carriers.¹³⁸

PMID 27496084: In a National Cancer Institute Li-Fraumeni syndrome cohort of germline TP53 mutation carriers, adrenocortical carcinoma was included among the core LFS cancers and all five first ACC diagnoses occurred before age 18. The study supports hereditary TP53-related predisposition as an important ACC risk context, particularly in childhood.¹³⁹

PMID 27603373: This case report describes ACC in a man with a germline BRCA2 8765delAG founder mutation and strong family history of BRCA2-associated cancers. Tumor loss of heterozygosity at BRCA2 is presented as evidence supporting a possible hereditary predisposition context for ACC beyond the better-established syndromes.⁷⁴

PMID 27714481: In a Brazilian Li-Fraumeni and Li-Fraumeni-like cohort, adrenocortical carcinoma appeared within the TP53-associated tumor spectrum, and adrenocortical tumors were more prevalent in TP53-positive than TP53-negative families. The report also describes a pediatric ACC case carrying the germline TP53 R337H mutation.¹⁴⁰

PMID 27899191: This review states that adrenocortical carcinoma is rare, with an incidence of about 1 to 2 per million persons per year, and that roughly 10% of cases are associated with germline mutations. It highlights Li-Fraumeni syndrome, Lynch syndrome, MEN1, and more rarely familial adenomatous polyposis and Beckwith-Wiedemann syndrome as hereditary contexts linked to ACC.¹³

PMID 27965001: This review describes a possible association between Beckwith-Wiedemann syndrome and calcifying nested stromal-epithelial tumor of the liver, while noting that Beckwith-Wiedemann syndrome is already linked to increased risk of embryonal tumors including adrenocortical carcinoma. It also emphasizes molecular subtype-specific tumor risk variation within Beckwith-Wiedemann syndrome.⁴⁵

PMID 28070481: This case report describes cortisol-secreting ACC arising in a patient with genetically confirmed MEN1, supporting MEN1 as a hereditary context in which adrenocortical malignancy can occur. The authors note that MEN1-related ACC may evolve from initially small adrenal tumors and may show loss of menin expression.⁵⁸

PMID 28756477: In Brazilian TP53 R337H mutation carriers from Li-Fraumeni or Li-Fraumeni-like families, ACC was one of the core associated tumors and occurred at very early age, with a median diagnosis age of 2.5 years. The study also examined p53-pathway polymorphisms as possible phenotype modifiers in this hereditary risk context.¹⁴¹

PMID 28819017: A four-patient case series describes ACC occurring in carriers of truncating SDHA or SDHC mutations, with germline involvement confirmed in three cases. The authors propose ACC may be a rare manifestation of SDHx-associated tumor syndromes, while emphasizing that current evidence is insufficient to justify targeted ACC surveillance in SDHx carriers.⁷⁵

PMID 28911001: This familial cancer study identifies adrenocortical carcinoma as part of the Li-Fraumeni syndrome tumor spectrum, describing a 4-year-old boy with metastatic ACC who carried a novel germline TP53 frameshift mutation inherited from his mother. The report reinforces hereditary TP53-related risk context for early-onset ACC.¹⁴²

PMID 28940135: This case report highlights Lynch syndrome as a hereditary risk context for ACC, including an ectopic retroperitoneal, nonfunctional presentation associated with germline MSH2 loss. The excerpt notes a reported Lynch syndrome prevalence of about 3.2% among ACC cases and discusses consideration of mismatch-repair testing in ACC.⁶⁰

PMID 29070607: This study supports Li-Fraumeni syndrome as an important hereditary context for ACC, especially in children, noting TP53 mutation detection rates of 45% to 66% in pediatric ACC and identifying additional de novo and mosaic TP53 mutation carriers among children with ACC.⁶

PMID 29768344: This case report describes a 29-year-old woman with sporadic ACC followed synchronously by an ovarian malignant mixed germ cell tumor, highlighting that ACC can rarely coexist with a second primary malignancy outside recognized familial syndromes. The report also notes hereditary risk context by discussing p53-associated syndromes and Lynch syndrome screening with mismatch repair immunohistochemistry.¹⁴³

PMID 29909163: This review identifies MEN1 as a rare hereditary syndrome in which adrenocortical tumors occur in about 20% to 40% of affected patients. Within MEN1, adrenal involvement is usually asymptomatic and nonfunctional, while adrenocortical carcinoma is described as rare.⁵⁰

PMID 29935265: This single-institution Li-Fraumeni syndrome series identifies adrenocortical carcinoma as one of the malignancies seen in TP53 mutation carriers and cites prior reports showing frequent germline TP53 alterations in ACC, especially in patients younger than 18 years. The article frames ACC as an established hereditary-syndrome–associated cancer within the TP53/Li-Fraumeni risk context.¹⁴⁴

PMID 30104051: This review summarizes hereditary cancer syndromes linked to ACC, emphasizing Li-Fraumeni syndrome in children and Lynch syndrome and MEN1 in adults. It notes that ACC can be the index malignancy prompting germline evaluation and family cascade testing, while absolute ACC risk in most carriers remains too low for broad ACC screening.¹¹

PMID 30181409: This case report describes incidentally detected, nonfunctional localized ACC in a young woman with familial adenomatous polyposis, highlighting FAP as an uncommon hereditary syndrome associated with adrenal neoplasms. The excerpt notes adrenal masses may be more frequent in FAP than in the general population, while adrenal tumor behavior appears comparable to sporadic cases.⁶⁸

PMID 30239254: This pediatric case report highlights adrenocortical tumor in infancy as a presentation that can prompt evaluation for Li-Fraumeni syndrome, describing a novel germline TP53 p.Gly187Arg variant in a family with early-onset cancers. The report reinforces hereditary TP53-associated risk context for pediatric adrenocortical neoplasms.¹⁴⁵

PMID 30721134: This kindred report and literature review supports MEN1 as a rare hereditary context for ACC, describing familial aggregation, a pooled prevalence of 18 cases among 1187 MEN1 patients, and younger age at diagnosis than sporadic ACC. Adrenal lesions are common in MEN1, but most are benign adenomas or hyperplasia rather than carcinoma.⁵¹

PMID 30915114: In a 10-year single-center Chinese cohort of endogenous Cushing’s syndrome, adrenocortical carcinoma accounted for 1.0% of cases, showed a marked female predominance with a 4.3:1 ratio, and most often presented in patients aged 40-59 years.¹⁴⁶

PMID 30963136: This case report and literature review highlights Lynch syndrome, including MSH6 mutation carriers, as a rare hereditary context for ACC and notes a reported 3.2% prevalence of Lynch syndrome among ACC patients in one prospective series. It emphasizes that ACC may be the only manifestation of Lynch syndrome and that optimal case-detection strategies remain uncertain.⁶¹

PMID 30974190: In a Brazilian Li-Fraumeni/Li-Fraumeni-like cohort, the germline TP53 p.R337H variant was common in pediatric adrenocortical tumors and also present in a minority of adults with ACC. The study supports hereditary risk context for ACC, with age-related differences in prevalence and tumor behavior among mutation carriers.¹⁴⁷

PMID 30985498: This review states that all patients with adrenocortical carcinoma should undergo TP53 germline testing and microsatellite instability assessment, reflecting ACC’s association with inherited cancer syndromes. It highlights Li-Fraumeni syndrome and Lynch syndrome as key hereditary contexts, with additional rarer links to MEN1, familial adenomatous polyposis, Beckwith-Wiedemann syndrome, and neurofibromatosis type 1.¹⁴

PMID 31045926: This review notes that adrenocortical carcinoma is a rare cancer with an incidence of 1-2 cases per million annually and poor prognosis, and it highlights small studies suggesting a possible predisposition in Lynch syndrome, an association described as less well studied than in Li-Fraumeni syndrome.⁸³

PMID 31241762: In a hospital-based case-control study, ACC risk was associated with cigarette smoking in men and with family history of cancer in both sexes, while alcohol use was associated with lower risk in men. The article also reiterates that most adult ACC is sporadic, with a minority linked to hereditary cancer syndromes.¹⁴⁸

PMID 31511974: This review identifies Li-Fraumeni syndrome as a major hereditary risk context for ACC, listing ACC among the core LFS tumors and noting that ACC can itself trigger TP53 germline testing regardless of family history. The excerpt also states that ACC is associated with LFS in about half of cases.²⁸

PMID 33327514: The review identifies adrenocortical carcinoma as a TP53 core tumor within Li-Fraumeni syndrome and notes that childhood ACC is a clinical context strongly suggestive of a germline TP53 alteration, including possible mosaicism, even without a marked family history.⁷

PMID 33363659: This case report describes adrenocortical carcinoma arising in a woman with neurofibromatosis type 1, alongside gastrointestinal stromal tumor and prior endometrial cancer. The authors note that ACC can occur in inherited cancer syndromes and that only a small number of ACC cases with NF-1 have been reported.⁷⁶

PMID 33615670: This case report describes metastatic ACC in a patient with germline MSH2 and RET mutations, with clinical features and family history most consistent with Lynch syndrome. The authors note prior data linking ACC to Lynch syndrome and suggest ACC may warrant consideration within Lynch surveillance and diagnostic frameworks.¹⁴⁹

PMID 33704190: This case report highlights Li-Fraumeni syndrome as an inherited risk context for ACC, emphasizing that ACC is a core LFS-related cancer but that adult-onset LFS-associated ACC is uncommon and less well characterized than pediatric cases. It describes an adult patient with a germline TP53 mutation and multiple primary malignancies including metastatic ACC.¹⁵⁰

PMID 34510813: This review and two-case report support Beckwith-Wiedemann syndrome as a hereditary risk context for pediatric adrenocortical tumors, highlighting particularly elevated tumor risk with paternal uniparental disomy of chromosome 11. One infant with mosaic UPD(11)pat developed adrenocortical carcinoma during follow-up, underscoring genotype-guided surveillance.⁴⁰

PMID 34630667: This review identifies Carney complex as a rare hereditary syndrome linked mainly to PRKAR1A alterations and notes that adrenal cortical tumors in this setting are usually benign, with only a few reported adrenocortical carcinoma cases. It places ACC within inherited adrenal tumor predisposition alongside other syndromic contexts.⁷²

PMID 34660377: This case report highlights that ACC can occur in a young adult without an identifiable familial cancer syndrome and notes that ACC is associated with several hereditary syndromes. It also states that a subset of apparently nonfamilial ACC cases have other malignancies before or after ACC diagnosis, while the reported coexistence with intracranial myoepithelioma appears coincidental.¹⁵¹

PMID 34934446: This review identifies Li-Fraumeni syndrome as a hereditary risk context for adrenocortical carcinoma, noting that ACC is a prominent early-life tumor in TP53 mutation carriers. It states that 50-80% of infancy ACC cases are associated with syndromic TP53 mutations, while about 10% of adult ACC cases have a genetic anomaly such as Li-Fraumeni or Lynch syndrome.¹⁵²

PMID 35221658: This case report describes adrenocortical carcinoma arising in a patient with genetically confirmed Birt-Hogg-Dubé syndrome due to an FLCN mutation. The authors note only a small number of prior adrenal tumors reported in this syndrome and suggest adrenal tumors may belong to the BHDS tumor spectrum.⁷⁷

PMID 35232817: This case report reinforces Li-Fraumeni syndrome as an inherited cancer predisposition context for adrenocortical carcinoma and describes a rare germline TP53 intragenic tandem duplication causing loss of function. It highlights that copy-number TP53 alterations can underlie TP53-related cancer susceptibility, not only sequence variants.¹⁵³

PMID 35543639: This pediatric case highlights the strong association between adrenocortical carcinoma and Li-Fraumeni syndrome in children, noting that germline TP53 mutations occur in a large proportion of pediatric ACC and may warrant syndrome evaluation when ACC coexists with other early-onset malignancies.¹⁵⁴

PMID 35946080: This case report describes ACC arising in a patient with Birt-Hogg-Dubé syndrome due to a pathogenic germline FLCN mutation, suggesting adrenal cortical tumors may belong to the syndrome’s tumor spectrum. The authors note only a few prior adrenal lesions have been reported in Birt-Hogg-Dubé syndrome, underscoring a possible but very rare hereditary association.⁷⁸

PMID 35974385: In Li-Fraumeni syndrome and the broader Li-Fraumeni spectrum caused by germline TP53 variants, adrenocortical carcinoma appears as a distinctive childhood-associated tumor. In this registry analysis, partially functional TP53 variants were associated with cancer-free childhood except for childhood ACC, which could occur as the only childhood cancer in some families.¹⁵⁵

PMID 36529791: This review notes adrenocortical carcinoma as a characteristic Li-Fraumeni syndrome spectrum tumor and states that TP53 mutation testing should be pursued when ACC occurs regardless of family history. It also describes a family carrying the Brazilian germline TP53 p.R337H variant in which a child developed ACC.²⁹

PMID 36701047: This case report supports a possible hereditary risk context for ACC in Birt-Hogg-Dubé syndrome, describing a functional metastatic ACC in a woman with a germline FLCN truncating variant and enrichment of the same variant in tumor tissue, alongside a brief literature summary of other reported adrenal cortical neoplasms in BHD.⁷⁹

PMID 36740703: This review highlights Carney complex as a hereditary syndrome linked to PRKAR1A mutations that can include primary pigmented nodular adrenocortical disease and ACTH-independent Cushing syndrome. In suspected syndromic cases with multiple endocrine and non-endocrine tumors, genetic testing is recommended.¹⁵⁶

PMID 36925187: This review notes that adrenocortical carcinoma can occur in hereditary contexts and names several associated syndromes, including Li-Fraumeni, Lynch, Beckwith-Wiedemann, familial adenomatous polyposis, MEN1, and Carney complex, supporting consideration of genetic counseling and germline testing in adrenal tumor care.¹⁶

PMID 37133731: This guideline identifies adrenocortical carcinoma as a core tumor in heritable TP53-related cancer syndrome and notes that ACC risk in carriers is concentrated in childhood, at about 4%, declining after the first decade of life. It also frames TP53 testing and surveillance as relevant in this hereditary risk context.²⁵

PMID 37508646: This pediatric case report links adrenocortical carcinoma to Li-Fraumeni syndrome caused by a novel germline TP53 frameshift variant and emphasizes that many childhood ACC cases harbor TP53 pathogenic variants. It highlights the importance of family history, genetic evaluation, and referral for surveillance in hereditary cancer predisposition.¹⁵⁷

PMID 37562436: This case series of Korean patients with Li-Fraumeni syndrome supports adrenocortical carcinoma as part of the syndrome’s core tumor spectrum, alongside breast cancer, sarcoma, and brain tumors. The report reinforces germline TP53–associated hereditary risk context rather than providing ACC-specific management or pathology details.¹⁵⁸

PMID 37577077: The case report notes Li-Fraumeni syndrome as a hereditary TP53-related cancer predisposition syndrome that includes adrenocortical carcinoma among its associated malignancies. It also highlights the Brazilian founder variant R337H as a disease-causing TP53 mutation relevant to this inherited risk context.¹⁵⁹

PMID 37859908: This case review identifies Li-Fraumeni syndrome as a rare inherited TP53-related cancer predisposition syndrome in which adrenocortical carcinoma is among the characteristic tumors. It emphasizes that absence of family history does not exclude the syndrome because de novo TP53 mutations can occur, supporting genetic counseling and testing when hereditary risk is suspected.¹⁶⁰

PMID 37966258: In a longitudinal rare-tumor cohort, adrenocortical carcinoma accounted for 18% of enrolled cases and was predominantly adult and female, with 86% of ACC participants being women. The study also identified TP53 and CTNNB1 mutations among ACC cases within a natural history and genomic data-collection framework.¹⁶¹

PMID 38108666: In a retrospective MEN1 cohort, adrenal lesions were identified in 23.3% of patients, while ACC was uncommon but present in 2.2% of those with adrenal lesions. The report supports MEN1 as a hereditary context in which adrenal lesions are frequent and lesion growth and size may help flag malignant potential.⁵²

PMID 38252880: In women with Carney complex, a hereditary endocrine neoplasia syndrome often linked to PRKAR1A pathogenic variants, this prospective cohort found breast carcinoma more frequently and at a younger age than in the general population. The excerpt also notes that adrenocortical carcinoma has been reported in Carney complex, although its specificity remains debated because of small series.¹⁶²

PMID 38412388: In a multicenter pedigree analysis of 146 TP53-positive families, adrenocortical carcinoma was confirmed as one of the core Li-Fraumeni syndrome cancers with among the highest hazard ratios. The study reinforces TP53 pathogenic variants as a major hereditary risk context for ACC.¹⁶³

PMID 38532453: This review summarizes hereditary cancer predisposition syndromes linked to ACC, emphasizing a strong association with Li-Fraumeni syndrome in pediatric ACC, weaker links in adults, and additional reported associations with Lynch syndrome, familial adenomatous polyposis, and Beckwith-Wiedemann syndrome.¹²

PMID 38714106: In a retrospective two-center series of 150 adults with presumed sporadic ACC, targeted germline NGS identified pathogenic or likely pathogenic variants in 6.7% of patients, including novel TP53 and ARMC5 variants. These findings indicate that clinically sporadic adult ACC can still harbor heritable susceptibility variants relevant to genetic counseling.¹⁰

PMID 38765733: This case report highlights Li-Fraumeni syndrome as an inherited TP53-related cancer predisposition context for ACC, noting that approximately 3%–10% of LFS-associated cancers are ACC and that germline TP53 mutations substantially increase relative risk. It also underscores the importance of genetic counseling and family history review when early-onset or multiple primary tumors are present.¹⁶⁴

PMID 39072610: This case report notes that adrenocortical carcinoma is among the cancers most frequently associated with Li-Fraumeni syndrome, an autosomal dominant cancer predisposition caused by pathogenic germline TP53 variants. It reinforces hereditary syndrome context as an important risk setting for ACC.¹⁶⁵

PMID 39100628: This case report situates ACC within Li-Fraumeni syndrome, a germline TP53 cancer predisposition syndrome, and notes that LFS-associated ACC typically presents in early childhood, with adult-onset TP53-variant ACC appearing enriched in patients younger than 40 years. It highlights hereditary risk context rather than general ACC management.¹⁶⁶

PMID 39217593: This case report identifies Carney complex due to a PRKAR1A mutation as a hereditary context involving adrenocortical disease, with prior cortisol-producing adrenal adenoma in a patient later recognized to have a syndromic tumor predisposition. It underscores the role of genetic evaluation when rare endocrine and non-endocrine tumors cluster in one patient.¹⁶⁷

PMID 39388056: This review highlights hereditary risk context for ACC, emphasizing frequent germline predisposition in childhood disease, much lower prevalence in adults, and key associated syndromes including Li-Fraumeni, Lynch, and Beckwith-Wiedemann, with rarer links to MEN1, APC, NF1, SDH, PRKAR1A, and BRCA2.³

PMID 39571462: This case report describes a Lynch syndrome kindred with two ACC cases and reviews prior reports suggesting ACC is a Lynch-associated malignancy, with MSH2 mutations appearing overrepresented among reported cases. The authors argue that Lynch patients with a close relative affected by ACC may warrant consideration of adrenal screening.⁶⁵

PMID 39600484: This letter identifies Li-Fraumeni syndrome as an inherited TP53-associated cancer predisposition syndrome that includes adrenocortical carcinoma within its tumor spectrum. It notes that ACC can itself meet Chompret diagnostic criteria for Li-Fraumeni syndrome regardless of family history, underscoring the need for genetic counseling and surveillance.³⁵

PMID 39608104: This case report describes the first reported extra-adrenal ACC in a patient with MEN1 and emphasizes that adrenal lesions in MEN1 may carry meaningful malignant potential. The authors recommend recognizing at-risk patients, pursuing MEN1 evaluation when clinical features suggest the syndrome, and closely following newly identified adrenal lesions with short-interval imaging and a lower threshold for surgery.⁵³

PMID 40063153: The review identifies Li-Fraumeni syndrome as a rare hereditary cancer syndrome, predominantly linked to germline TP53 mutations, in which adrenocortical carcinoma is one of the classically associated neoplasms. It reinforces hereditary cancer predisposition as part of the risk context relevant to ACC.¹⁶⁸

PMID 40250894: This review summarizes ACC as a rare malignancy with annual incidence of 0.5 to 2 per million, bimodal age distribution, female predominance in adults, and marked pediatric clustering in southern Brazil linked to the TP53 R337H germline variant. It also highlights smoking, radiation exposure, and hereditary syndromes including Li-Fraumeni, Beckwith-Wiedemann, Lynch, and MEN1 as important risk contexts.²¹

PMID 40289692: Li-Fraumeni syndrome is a hereditary TP53-associated cancer predisposition syndrome that includes adrenocortical carcinoma within its core tumor spectrum. In children and adolescents with Li-Fraumeni syndrome, ACC is reported as a common malignancy, accounting for about 27% of tumors in this review.¹⁶⁹

PMID 40542714: This review identifies Li-Fraumeni syndrome, caused by germline TP53 variants, as a hereditary cancer predisposition syndrome in which adrenocortical carcinoma is a core tumor type. It highlights surveillance recommendations for TP53 carriers, especially pediatric adrenal monitoring with abdominal ultrasound and, when imaging is inadequate, steroid or biochemical testing.³⁶

PMID 40757052: This case report highlights Li-Fraumeni syndrome as a hereditary cancer predisposition syndrome strongly associated with adrenocortical carcinoma and emphasizes germline TP53 pathogenic variants as a key inherited risk context requiring lifelong surveillance from a young age.¹⁷⁰

PMID 40830167: This article reports a germline TP53 oligomerization-domain in-frame deletion that functionally abolishes p53 activity and is associated with Li-Fraumeni syndrome, a hereditary cancer predisposition syndrome that includes adrenocortical carcinoma. The study also contextualizes TP53 oligomerization defects alongside the R337H variant linked to pediatric adrenocortical carcinoma.¹⁷¹

PMID 41348740: This article links pediatric ACC to hereditary risk context by identifying a germline TP53 p.T253I variant in an infant with stage 1 ACC and providing functional evidence that the variant is pathogenic and may underlie Li-Fraumeni syndrome. The report reinforces TP53-associated cancer predisposition as an important consideration in pediatric ACC.¹⁷²

PMID 41440226: This review identifies hereditary context as a key modifier of ACC care, highlighting universal TP53 germline testing in ACC and the relevance of Li-Fraumeni syndrome to surveillance and treatment planning.¹⁷

PMID 41442053: In a Brazilian Li-Fraumeni syndrome cohort with germline TP53 pathogenic variants, adrenocortical carcinoma is identified as one of the core tumors in the syndrome spectrum. The report also notes that pediatric and adolescent TP53 carriers in this cohort showed expected tumors such as adrenocortical carcinoma, reinforcing its hereditary risk context.¹⁷³

PMID 41524568: This retrospective tertiary-center cohort supports Lynch syndrome as a hereditary risk context for ACC, estimating LS prevalence among ACC at 2.6%. LS-associated ACC occurred at mean age 44 years, showed near-equal sex distribution, and was most often linked to germline MSH2 or MSH6 pathogenic variants.⁶²

PMID 16033918: A 2006 letter on germline TP53 p.R337H reported penetrance data for adrenocortical tumors in carriers, indicating that risk is increased but incomplete. This refines the Brazilian founder-variant discussion by emphasizing variant-specific and population-specific heterogeneity within TP53-associated ACC predisposition.³³

PMID 22112814: A 2012 case report described a large family with Carney complex due to a PRKAR1A S147G mutation in which adrenocortical cancer occurred, providing direct but still low-level evidence that ACC can rarely fall within the Carney complex spectrum.⁷¹

PMID 24169328: A MEN2A pedigree series found frequent RET codon 634 mutations and substantial pheochromocytoma burden, supporting the broader principle that hereditary endocrine syndromes have distinct adrenal tumor spectra. For this ACC note, the article is relevant mainly as a caution against extrapolating adrenal pheochromocytoma predisposition to adrenocortical carcinoma risk.⁸¹

PMID 2876110: A 1986 MEN1 case report described adrenocortical hyperplasia together with renal cell carcinoma rather than ACC. It indirectly supports the note’s framing that MEN1 often includes adrenal abnormalities, but does not materially increase evidence for MEN1-associated ACC risk.⁵⁴

PMID 32373953: A case report of recurrent hepatocellular carcinoma in non-classic congenital adrenal hyperplasia is only indirectly relevant to ACC, but its review notes that adrenocortical tumors are described in congenital adrenal hyperplasia and that ACC has been reported only occasionally, including in non-classic disease.¹⁷⁴

PMID 15168774: A 2004 case report of suspected MEN1 described primary hyperparathyroidism with an aldosterone-producing adrenocortical adenoma and found no MEN1-locus loss of heterozygosity in the adrenal tumor. For ACC context, it indirectly supports the note’s framing that MEN1 is more often associated with nonmalignant adrenal cortical lesions than with established carcinoma predisposition.⁵⁵

PMID 16684821: A Finnish APECED series describes AIRE-related hereditary autoimmunity with frequent adrenocortical failure and multiple endocrine manifestations, but not ACC as a recognized syndrome component. For this note, the article is indirectly relevant because it helps distinguish inherited adrenal insufficiency syndromes from true hereditary ACC predisposition contexts.⁸⁰

PMID 22267170: A veterinary case report described a dog with adrenocortical carcinoma and other endocrine neoplasms as a possible MEN variant. For this note, it is only indirectly relevant because it broadens comparative syndromic context without adding direct evidence for human hereditary ACC risk.¹⁷⁵

PMID 32249909: A case report in FH-related hereditary leiomyomatosis and renal cell carcinoma described a cortisol-secreting adrenocortical adenoma with PPNAD-like features, but not ACC, and found no clear tumor-level evidence that FH loss drove the adrenal lesion. This supports only a cautious, indirect mention of FH/HLRCC as a possible adrenal cortical association rather than an established hereditary ACC syndrome.¹⁷⁶

PMID 9260769: A 1997 case report described ACTH-independent macronodular adrenocortical hyperplasia with multiple colorectal adenomas/carcinomas and an APC mutation detected in colon cancer but not in adrenal tissue. For ACC, this is indirect evidence that fits the note’s cautious treatment of APC/FAP-related adrenal associations rather than strengthening APC as a major ACC predisposition context.¹⁷⁷

PMID 25628771: A Chinese MEN2 cohort described RET-defined disease dominated by medullary thyroid carcinoma and adrenal pheochromocytoma, with use of cortical-sparing adrenalectomy for pheochromocytoma management. For ACC context, the report is indirectly relevant because it reinforces that hereditary adrenal involvement in MEN2 is not evidence of adrenocortical carcinoma predisposition.⁸²

PMID 33936872: A case report of lung squamous cell carcinoma in McCune-Albright syndrome briefly cites GNAS as an oncogenic driver reported in ACC, but provides only indirect support and does not establish McCune-Albright syndrome as a recognized hereditary ACC setting.⁸⁴

PMID 41113712: A 2025 adrenal incidentaloma sequencing study used a broad custom germline panel that included several genes discussed in hereditary ACC contexts, including APC, PRKAR1A, and GNAS. Its ACC relevance is indirect, but it highlights how adrenal genetics panels may extend beyond syndromes with well-established ACC risk.²²

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Hereditary Risk and Syndromic Context of ACC

Diagnostic and biologic context

Major hereditary syndromic settings

Lynch syndrome, FAP, Carney complex, and other rarer associations

Clinical implications, surveillance, and research limits

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References

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Hereditary Risk and Syndromic Context of ACC

Diagnostic and biologic context

Major hereditary syndromic settings

TP53-related syndromes and Li-Fraumeni spectrum

Beckwith-Wiedemann syndrome and 11p15-related overgrowth disorders

MEN1 and related endocrine neoplasia settings

Lynch syndrome, FAP, Carney complex, and other rarer associations

Clinical implications, surveillance, and research limits

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References

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