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hereditary_and_syndromic_acc

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Hereditary and Syndromic ACC

Special Populations

Hereditary and syndromic adrenocortical carcinoma (ACC) refers to ACC arising in the setting of a germline cancer-predisposition syndrome or a broader inherited endocrine or overgrowth disorder. Within ACC care, this topic sits at the intersection of pediatric adrenal oncology, hereditary cancer genetics, endocrine tumor diagnosis, and family-based surveillance. The clearest and most clinically important association is with germline TP53 alteration and Li-Fraumeni syndrome, particularly in children, while other recognized settings include Beckwith-Wiedemann spectrum and, less consistently, MEN1, Carney complex, and related cAMP-pathway disorders.1234

Hereditary context matters because it may alter the likelihood that an adrenal tumor represents ACC, the age-specific differential diagnosis, and the need for counseling and surveillance in relatives. In pediatric practice, ACC may be the presenting malignancy that leads to recognition of an underlying syndrome, and germline susceptibility may be identified even when family history is limited or apparently negative.156 However, many hereditary syndromes associated with adrenal abnormalities more often produce benign adenomas, micronodular or macronodular hyperplasia, or other non-ACC lesions, so syndromic status alone does not establish malignancy.789

The evidence base is uneven and relies heavily on retrospective pediatric series, founder-mutation cohorts, reviews, and case reports. Prospective comparative data are limited, penetrance estimates remain uncertain for many syndromes, and the generalizability of single-center or regional experiences is often restricted.1011124 As a result, most management principles are extrapolated from sporadic ACC, pediatric oncology practice, and general hereditary cancer care rather than from syndrome-specific trials.

Diagnostic context

Hereditary predisposition is most strongly established in pediatric ACC, which differs from adult disease in age distribution, endocrine presentation, and frequency of germline susceptibility.10313 Childhood tumors often present before age 5 and are commonly hormonally active, particularly with virilization, mixed androgen-cortisol excess, or overt Cushing syndrome.101114 In this setting, very young age, hormone-producing presentation, multiple primary tumors, or associated overgrowth or endocrine features should increase suspicion for an inherited disorder.1153

What is relatively reliable is that pediatric ACC warrants a low threshold for germline evaluation, especially for TP53-related disease.1164 What is less reliable is the use of clinical phenotype alone to identify the specific syndrome or to distinguish carcinoma from benign syndrome-related adrenal lesions; integrated endocrine, imaging, pathologic, and genetic assessment remains necessary.10174

This diagnostic framework helps explain why the major hereditary settings are best considered by the strength of their association with carcinoma itself and by the adrenal lesions they more commonly produce.

Major hereditary settings

Li-Fraumeni syndrome and TP53-associated disease

Li-Fraumeni syndrome is the best-established hereditary ACC syndrome and dominates the pediatric hereditary literature.13 Constitutional TP53 variants are reported in a substantial proportion of pediatric ACC cases, including children without a strong family history, making TP53 testing a central component of hereditary assessment in this population.154 ACC may be the sentinel cancer in affected children or occur alongside other Li-Fraumeni spectrum tumors.181920

Regional founder effects, especially TP53 p.R337H in southern Brazil, further show that inherited background can strongly influence apparent ACC incidence in selected populations.112116 This association is sufficiently consistent to support routine hereditary evaluation, family counseling, and syndrome-aware surveillance in pediatric ACC.1184 By contrast, evidence that TP53 status independently changes standard ACC drug treatment or surgical strategy remains limited; its clearest clinical value is in earlier recognition and broader cancer-risk management.2212

Beckwith-Wiedemann spectrum and overgrowth phenotypes

Beckwith-Wiedemann spectrum is another recognized hereditary context, particularly in fetal, neonatal, and early-childhood adrenocortical tumors.231524 Overgrowth, hemihypertrophy, placental abnormalities, and very early presentation may accompany adrenal cortical neoplasia in this setting.2523 The most dependable conclusion is that these features increase concern for adrenal cortical tumorigenesis in infants and young children.1011

Less dependable is any assumption that an adrenal mass in Beckwith-Wiedemann spectrum is necessarily ACC, because benign mimics and overlapping imaging appearances have been reported.17 The practical implication is that affected patients generally require specialist multidisciplinary review rather than simplified incidentaloma-style management.

MEN1 and Carney complex are relevant mainly because they broaden the hereditary differential for adrenal disease, but their association with frank ACC is much weaker than that of TP53-related disease.729 In MEN1, adrenal lesions are relatively common but are usually benign, nonfunctioning, or hyperplastic; ACC appears uncommon, though likely more frequent than in the general population.26279 In Carney complex, the typical adrenal phenotype is primary pigmented nodular adrenocortical disease (PPNAD) or related hyperplasia rather than carcinoma.7828

These syndromes are diagnostically important because they create difficult benign-malignant differentials. PPNAD may cause ACTH-independent Cushing syndrome despite subtle or normal adrenal imaging, and Carney-complex-spectrum adenomas or macronodules may clinically resemble ACC.2930 Similarly, MEN1-associated adrenal lesions may be followed over time because most are not malignant, yet rare ACC can occur.2731

What is reliable is that MEN1 and Carney complex justify syndrome-aware evaluation of adrenal lesions. What is not reliable is using the syndrome label alone to infer high absolute ACC risk. In practice, management still depends primarily on lesion size, hormonal activity, growth, and pathology rather than on hereditary context alone.79

Rare or uncertain associations

Additional hereditary contexts, including familial adenomatous polyposis and isolated reports in other syndromic settings, have been described but remain weakly supported.232 These reports mainly provide biologic plausibility or historical context and do not establish major ACC predisposition syndromes or routine syndrome-specific screening pathways.

Hormonal phenotypes and differential diagnosis

Across hereditary and syndromic ACC, hormone excess is a major clinical clue, especially in children. Virilization, mixed androgen and cortisol secretion, and overt Cushing syndrome are the most reproducible endocrine patterns.1053 Neonatal and infant presentations may include abdominal mass, rapid growth, hypertension, or severe hypercortisolism, while some tumors are detected during surveillance and may be less overtly functional.152422

Rare functional phenotypes may complicate recognition. Aldosterone-producing ACC is uncommon and may mimic a small functional adenoma, and feminizing or mixed-secretory tumors further broaden the endocrine spectrum.333435 At the same time, hereditary benign lesions such as PPNAD may mimic carcinoma in patients with hypercortisolism.2928 The practical implication is that complete steroid evaluation and syndrome-aware differential diagnosis are more reliable than reliance on a single hormonal pattern.

This endocrine variability leads directly to the main management issue: hereditary classification usually informs risk assessment and surveillance more than it changes core anticancer treatment.

Management implications and outcomes

When ACC is diagnosed, management remains centered on complete surgical resection when feasible, as in sporadic disease.3654 Pediatric and hereditary recognition may improve outcomes indirectly by enabling earlier detection of localized tumors, but advanced-stage disease still carries poor prognosis, and there is little evidence that inherited status alone changes standard surgical or systemic treatment algorithms.371813

The strongest practical role of hereditary classification is therefore in genetic counseling, family testing, and surveillance planning rather than in syndrome-specific ACC therapy.123 This is especially well supported in pediatric ACC and in patients with suggestive personal or family histories, syndromic features, or multiple primary tumors.164 Evidence for tailored adjuvant therapy, prognosis, or surveillance intervals based specifically on hereditary subtype remains limited and largely retrospective.124

Limitations and research needs

Several limitations recur across this literature. Pediatric histopathologic criteria differ from adult practice, syndrome-related hyperplasia may mimic neoplasia, and case reports may overstate the importance of very rare associations.10154 Founder-mutation series and tertiary-center cohorts also may not generalize to broader ACC populations.1116

The most consistent overall conclusion is that hereditary ACC is heterogeneous. TP53-related disease has the clearest link to carcinoma itself, whereas other syndromes more often increase the frequency of adrenal abnormalities in general and only occasionally ACC.734 Current research is focused more on clarifying risk stratification and surveillance than on developing syndrome-specific therapies, reflecting the rarity of these conditions and the continued dependence on retrospective data.124

Included Articles

  • PMID 2231941: This case report describes an aldosterone-producing adrenocortical carcinoma in a patient with XY/XXY mosaic Klinefelter syndrome, presenting as isolated severe primary aldosteronism without Cushingoid or feminizing features. The report suggests this association is rare and highlights successful surgical management with short-term biochemical normalization.38
  • PMID 3390790: This neonatal case report describes congenital ACC with skin and brain metastasis, mild steroid excess without overt virilization, subsequent hemihypertrophy, and spontaneous regression of metastatic lesions after resection of the adrenal primary alone. The report also notes possible association with an incomplete Beckwith-Wiedemann syndrome phenotype.25
  • PMID 8588274: This case report and literature review highlights isolated primary aldosteronism as a rare functional presentation of adrenocortical carcinoma, reported in only a small minority of ACC cases. It emphasizes that aldosterone-producing ACC can mimic benign adenoma, including in a small 3 cm adrenal mass, making this an unusual hormonal variant.33
  • PMID 10464805: This review summarizes the distinctive pediatric profile of adrenocortical neoplasms: most occur before age 5, often in girls, are commonly hormone-secreting with virilization or mixed Cushing features, and are linked to syndromes such as Beckwith-Wiedemann and Li-Fraumeni. It also notes that pediatric tumors differ from adult lesions in biology, prognosis, and the difficulty of distinguishing adenoma from carcinoma histologically.10
  • PMID 11004724: This review summarizes pediatric adrenocortical tumors as a distinct ACC-related population characterized by very young age at presentation, female predominance, frequent virilizing or mixed endocrine syndromes, marked incidence excess in Southern Brazil, and associations with Li-Fraumeni and Beckwith-Wiedemann syndromes.11
  • PMID 12460368: This case report describes an uncommon aldosterone-producing ACC presenting with hypokalemia and hypertension, with postoperative normalization of aldosterone followed by rapid metastatic recurrence associated with new ACTH-suppressed hypercortisolism. It highlights that ACC can show unusual steroid phenotypes and a changing hormonal profile over time.39
  • PMID 15387874: This case report describes pregnancy-associated ACC presenting at 18 weeks with severe secondary hypertension, hypokalemic alkalosis, hyperglycemia, and a large cortisol-secreting adrenal mass. It highlights the diagnostic difficulty of recognizing Cushing’s syndrome during pregnancy because physiologic gestational cortisol changes can obscure standard testing.40
  • PMID 16132517: This review highlights pediatric ACC as a distinct setting characterized by frequent hormone excess, especially virilization, associations with inherited cancer syndromes such as Li-Fraumeni, and rare but clinically relevant brain metastases. It also describes an unusual NF-1 case in which intracranial lesions mimicked metastases but represented NF-1-related hamartomatous changes.41
  • PMID 16197716: In pediatric adrenocortical carcinoma, constitutional TP53 mutations are reported in roughly 50% to 80% of cases, often even without a strong family history. The review highlights pediatric ACC as a malignancy that warrants genetic evaluation because of links to Li-Fraumeni syndrome and implications for surveillance of patients and relatives.1
  • PMID 16254889: This case report describes prenatal and neonatal presentation of fetal bilateral adrenocortical carcinoma, including ultrasonographic detection of large complex bilateral abdominal masses with polyhydramnios, placental enlargement, and fetal overgrowth. The findings also raise a possible association with an incomplete Beckwith-Wiedemann syndrome phenotype.23
  • PMID 16458846: This pediatric review highlights that childhood ACC is rare, often hormonally active with virilization and/or Cushing syndrome, and has distinctive hereditary associations including TP53-related Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. It also emphasizes pediatric-specific management considerations such as resection of incidental adrenal masses and the primacy of complete surgical excision.36
  • PMID 17234769: This pediatric adrenocortical tumor study describes childhood disease as rare, often hormonally active, and associated with hereditary syndromes including Li-Fraumeni, Beckwith-Wiedemann, Carney complex, and MEN1. It also notes poor outcomes for advanced pediatric cases and similarities in gene-expression patterns between pediatric and adult adrenocortical carcinomas.37
  • PMID 17578766: This review highlights Carney complex and related bilateral adrenal hyperplasias as hereditary contexts linked to adrenocortical tumorigenesis, including PPNAD and associations with syndromic conditions such as MEN1, FAP, and McCune-Albright syndrome. It emphasizes inherited and low-penetrance genetic factors including PRKAR1A and PDE11A.7
  • PMID 19101993: This pediatric case report describes asymptomatic stage I adrenocortical carcinoma detected during surveillance in a child with Li-Fraumeni syndrome and a germline TP53 Tyr220Cys mutation. It emphasizes hereditary-risk follow-up, genetic counseling, and consideration of lower-radiation surveillance approaches in children.18
  • PMID 20334485: This review of fetal and newborn adrenocortical tumors highlights that neonatal ACC often presents with an abdominal mass and is usually hormonally active, with virilization, Cushing syndrome, or hypertension more common than in older patients. It also notes frequent metastatic presentation, uncertain histologic malignancy criteria in this age group, and associations with Beckwith-Wiedemann syndrome, hemihypertrophy, and Li-Fraumeni-related cancer family syndromes.15
  • PMID 20833338: This review highlights familial and pediatric adrenocortical tumors, emphasizing inherited predisposition syndromes such as TP53-related Li-Fraumeni, MEN1, APC, PRKAR1A, and Beckwith-Wiedemann syndrome. It also summarizes pediatric presentation, diagnostic evaluation, and management differences, including preference for open adrenalectomy and uncertain chemotherapy benefit in children.2
  • PMID 22312093: This editorial discusses rare cases of adrenocortical carcinoma arising in patients with Carney complex and background primary pigmented nodular adrenocortical disease, highlighting cortisol-androgen co-secretion, possible progression from PPNAD, and the need to consider ACC when large macronodules or androgen excess are present in this hereditary syndrome.28
  • PMID 22355500: This case report describes a rare aldosterone-secreting ACC in a 31-year-old man with synchronous papillary thyroid carcinoma, highlighting an unusual endocrine phenotype and a possible hereditary-cancer context despite negative TP53 and menin testing. It underscores that primary hyperaldosteronism is an uncommon presentation of ACC.42
  • PMID 23065993: This case report describes virilization, infertility, and subclinical ACTH-independent Cushing syndrome caused by a PPNAD-associated adrenal adenoma with a PRKAR1A truncating mutation in the setting of Carney complex-spectrum disease. It highlights an unusual hereditary adrenal context that can clinically mimic adrenocortical carcinoma.30
  • PMID 23255991: This case report discusses pregnancy-associated hypercortisolism from an adrenal tumor, highlighting that cortisol-secreting adrenal lesions in pregnancy can mimic physiologic changes and may raise concern for ACC. It describes multidisciplinary evaluation and successful laparoscopic adrenalectomy with low-pressure pneumoperitoneum during the second trimester.43
  • PMID 25097324: This case report highlights pregnancy-associated ACC as a diagnostic challenge because physiologic hormonal changes and imaging constraints can obscure recognition. It emphasizes that Cushing syndrome with virilization is a typical presentation in this setting, MRI is the preferred imaging modality, and second-trimester surgery is generally favored within multidisciplinary care.44
  • PMID 25148739: This national Italian pediatric series of adrenocortical tumors found that endocrine manifestations, especially virilization, were the commonest presentation, complete excision was central to cure, and younger age and tumor volume under 200 cm3 were associated with better outcomes. TP53 mutations were more frequent in malignant tumors and occasionally identified Li-Fraumeni syndrome even in tumors classified as benign.5
  • PMID 25550997: In Beckwith-Wiedemann syndrome, an adrenal mass should raise concern for adrenocortical carcinoma, but rare benign mimics such as ovarian thecal metaplasia can occur and may show imaging features overlapping with ACC and pheochromocytoma, making histologic confirmation necessary.17
  • PMID 26125435: The review notes that aldosterone-producing ACC is a rare cause of primary aldosteronism, reported in about 1% of sporadic cases, and tends to present with profound hypokalemia, very high aldosterone levels, and sometimes concurrent cortisol or sex-steroid excess causing Cushing syndrome or virilization.34
  • PMID 27512421: This pregnancy-associated ACC case shows that cortisol-secreting disease can present as severe early hypertension and proteinuria mimicking preeclampsia. The report highlights diagnostic challenges of Cushing syndrome in pregnancy, multidisciplinary peripartum decision-making, and the particularly poor prognosis reported for ACC diagnosed during pregnancy or early postpartum.45
  • PMID 27523914: This case report describes an exceptionally rare ectopic adrenocortical carcinoma arising in the ovary, presenting postpartum with severe ACTH-independent Cushing syndrome and androgen/estrogen excess. It highlights ovarian ectopic adrenal tissue as a rare source of metastatic cortisol-producing ACC-like disease and notes pregnancy or postpartum timing as a possible aggravating context.46
  • PMID 27555782: This bioinformatics study addresses pediatric adrenocortical carcinoma, highlighting its rarity, frequent hormone-secreting presentation, and association with hereditary contexts such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. Network analysis identified candidate pediatric ACC biomarkers including CDK1, CCNB1, CDC20, and BUB1B, pending experimental validation.47
  • PMID 29403152: This pediatric ACC case highlights a rare feminizing presentation in a prepubertal boy, with gynecomastia and growth acceleration without virilization despite elevated estradiol, testosterone, and adrenal steroid precursors. The report also notes a germline TP53 mutation and discusses Li-Fraumeni syndrome implications for follow-up.48
  • PMID 29406000: This review highlights neonatal and infantile Cushing syndrome as a rare setting in which adrenal lesions are the most common cause of endogenous hypercortisolism, with adrenocortical tumors often malignant and frequently linked to germline TP53 alterations or syndromic contexts such as Li-Fraumeni and Beckwith-Wiedemann syndromes.24
  • PMID 29746440: This pediatric case report describes an infant with composite adrenocortical carcinoma and neuroblastoma carrying a germline TP53 mutation consistent with Li-Fraumeni syndrome. The authors note that pediatric ACC is strongly associated with TP53 germline alterations and recommend genetic testing in patients with ACC.6
  • PMID 30288393: This pediatric case describes adrenocortical carcinoma resected at age 2 in a child later found to carry a TP53 mutation consistent with Li-Fraumeni syndrome, followed years later by a second malignancy. The report highlights ACC occurring in a syndromic pediatric context rather than typical adult disease.19
  • PMID 30726455: This editorial highlights pediatric ACC in infancy as a presentation that requires rapid recognition of virilization and possible Cushing syndrome, especially in regions of Brazil with increased TP53 mutation prevalence. It emphasizes prompt adrenal imaging, steroid evaluation, and referral for complete surgical resection at specialized centers.21
  • PMID 32304390: This review summarizes pediatric adrenocortical tumors as a distinct clinical setting marked by very low incidence, strong links to germline TP53 alterations and Li-Fraumeni syndrome, frequent virilization or mixed hormone excess in young children, and pediatric-specific diagnostic, surveillance, and prognostic considerations.3
  • PMID 32671623: In a Brazilian pediatric tumor cohort from a region with high TP53 p.R337H prevalence, all three adrenocortical carcinoma cases carried the heterozygous mutation, reinforcing the strong link between pediatric adrenocortical tumors and this Li-Fraumeni-associated founder variant.16
  • PMID 33442112: This case report highlights an unusual hormonally atypical ACC phenotype in a young man: aldosterone-producing ACC with co-secretion of cortisol and estradiol, presenting as primary aldosteronism with hypokalemia, subclinical Cushing syndrome, and feminization. It emphasizes complete hormonal testing, preoperative steroid coverage when cortisol excess is present, and long-term follow-up using imaging and initially elevated hormones.35
  • PMID 35195585: This case report describes metastatic adrenocortical carcinoma occurring in a patient with MEN1 mutation, highlighting ACC as a rare manifestation of MEN1 syndrome. The report also notes nonfunctional biochemical testing despite widespread disease and documents concurrent MEN1-associated parathyroid and pancreatic lesions.26
  • PMID 35317446: This review summarizes pediatric ACC as a distinct clinical entity with frequent hormone-producing presentation, strong hereditary and molecular associations such as TP53-related syndromes, and management differences from adults, including less standardized adjuvant therapy and prognostic relevance of Weiss score and Ki-67.13
  • PMID 36179244: This case report describes a patient with MEN1 who had ipsilateral oncocytic ACC and aldosterone-producing adenoma, with MEN1 loss of heterozygosity in both tumors and a somatic KCNJ5 mutation confined to the adenoma. It highlights MEN1 as a rare hereditary context for ACC and for hormonally unusual coexistence with primary aldosteronism.27
  • PMID 36193741: This pediatric imaging consensus notes that childhood adrenocortical tumors are rare, more often malignant than focal cortical tumors in adults, and usually hormonally functional, commonly causing virilization with possible Cushing syndrome or hyperaldosteronism. It also highlights predisposition syndromes including Li-Fraumeni, Beckwith-Wiedemann, Carney complex, FAP, and MEN1.14
  • PMID 36387865: This review summarizes pediatric ACC as a biologically and clinically distinct form of ACC characterized by frequent hormone secretion, strong links to germline predisposition syndromes such as Li-Fraumeni and Beckwith-Wiedemann, and management largely extrapolated from adult protocols despite important prognostic and therapeutic differences.12
  • PMID 36457625: This pediatric case report links adrenocortical carcinoma with Li-Fraumeni syndrome due to a germline TP53 c.743G>A (p.Arg248Gln) mutation and describes a rare nonfunctioning presentation detected by surveillance imaging, yet already metastatic to liver and lung at diagnosis.22
  • PMID 39263332: This review summarizes pediatric adrenocortical carcinoma as a distinct clinical entity marked by frequent hormone-producing tumors, strong association with germline TP53 alterations and other predisposition syndromes, pediatric-specific diagnostic criteria such as the Wieneke system, and management principles centered on prompt surgery while avoiding primary-tumor biopsy and rupture.4
  • PMID 40307791: This pediatric ACC case describes a 5-year-old boy with mixed hormone excess causing Cushing syndrome and virilization, complicated by rare uric acid nephrolithiasis and postoperative adrenal insufficiency. The report also emphasizes pediatric-specific issues including Wieneke-based pathology interpretation, TP53/Li-Fraumeni evaluation, and long-term follow-up.49
  • PMID 40815376: This pediatric ACC case in a 19-month-old boy with Li-Fraumeni syndrome presented with virilization, androgen excess, and hypercortisolism, alongside synchronous choroid plexus carcinoma. The report highlights hereditary TP53-associated pediatric ACC and the role of whole-body imaging in detecting multiple primary malignancies and short-interval surveillance.20
  • PMID 41141223: In MEN1, ACC is uncommon but occurs more often than in the general population, while most adrenal lesions remain benign. This case and literature review highlight the diagnostic difficulty of adrenal lesions in MEN1, including rare bilateral disease, and summarize reported ACC incidence and female predominance in this hereditary syndrome.9
  • PMID 41393183: This case report describes bilateral cortisol-secreting adrenocortical carcinoma presenting with Cushing syndrome in a patient with a horseshoe kidney, highlighting how an unusual anatomic variant can complicate diagnostic interpretation, preoperative planning, and surgical approach. Unilateral adrenalectomy was associated with marked postoperative cortisol decline and symptomatic improvement.50
  • PMID 41806143: This case report in a patient with MEN1 highlights that adrenal incidentalomas in MEN1 are often nonfunctional and surveillance can be challenging, while suggesting MEN1 carriers may have increased risk of ACC. Comparative molecular analysis of coexisting adenoma and carcinoma showed shared variants but did not prove adenoma-to-carcinoma progression driven by MEN1 loss of heterozygosity.31
  • PMID 20058620: A small case series of PPNAD supports the note’s framing that Carney complex is more often associated with hyperplasia-like adrenal disease than ACC, while adding that syndrome manifestations may emerge at different times and warrant ongoing surveillance for other endocrine and cardiac lesions.8
  • PMID 9298884: A 1997 MEN1 case report described unusually aggressive gastric neuroendocrine tumors with fatal outcomes, including one patient who also had adrenocortical abnormalities and adrenal micronodular hyperplasia. For the ACC note, this is indirect evidence that MEN1-related endocrine disease can be more heterogeneous and clinically complex than a uniformly benign framing would imply.51
  • PMID 10810995: A veterinary case report described MEN-like multisite endocrine neoplasia in a ferret, including adrenocortical adenoma rather than ACC. Its relevance to hereditary ACC is indirect and mainly supports cautious interpretation of adrenal lesions in MEN-spectrum contexts.52
  • PMID 17016649: A veterinary report described a familial medullary thyroid carcinoma pedigree in dogs, analogous to FMTC/MEN2, in which one animal also had multinodular adrenocortical hyperplasia. The study does not provide direct evidence for hereditary ACC, but reinforces that adrenal findings may occur in MEN-spectrum settings without implying carcinoma.53
  • PMID 23575299: A case report described fatal pediatric extraintestinal adrenal malignancy in a patient with familial adenomatous polyposis. For this note, it adds a cautious, low-level signal that adrenal cortical malignancy may rarely arise in broader hereditary cancer syndromes outside the better-established TP53, Beckwith-Wiedemann, MEN1, and Carney complex settings.32
  • PMID 25034529: An osteosarcoma study on menin described MEN1 as a tumor-suppressor pathway with prior links to several cancers, including adrenocortical carcinoma. For hereditary ACC, this serves only as indirect mechanistic context supporting biologic plausibility in MEN1 rather than direct evidence of syndrome-specific ACC risk.54
  • PMID 8964212: A 1996 case report of PPNAD described ACTH-independent Cushing syndrome with normal adrenal imaging, initial suspicion of adenoma or carcinoma, and recurrence after unilateral adrenalectomy before bilateral disease was confirmed pathologically. The report also noted possible Carney complex context, reinforcing PPNAD as an important syndromic mimic of ACC in the differential diagnosis.29

References

Footnotes

  1. Inherited susceptibility for pediatric cancer.. Cancer J. 2005. PMID: 16197716. Local full text: 16197716.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8 ↩9 ↩10

  2. Familial predisposition to adrenocortical tumors: clinical and biological features and management strategies.. Best Pract Res Clin Endocrinol Metab. 2010. PMID: 20833338. Local full text: 20833338.md ↩ ↩2 ↩3 ↩4 ↩5

  3. Pediatric adrenocortical tumor - review and management update.. Curr Opin Endocrinol Diabetes Obes. 2020. PMID: 32304390. Local full text: 32304390.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8

  4. Pediatric Adrenocortical Carcinoma: The Nuts and Bolts of Diagnosis and Treatment and Avenues for Future Discovery.. Cancer Manag Res. 2024. PMID: 39263332. Local full text: 39263332.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8 ↩9 ↩10 ↩11 ↩12 ↩13

  5. Adrenocortical tumors in Italian children: analysis of clinical characteristics and P53 status. Data from the national registries.. J Pediatr Surg. 2014. PMID: 25148739. Local full text: 25148739.md ↩ ↩2 ↩3 ↩4 ↩5

  6. Composite Adrenocortical Carcinoma and Neuroblastoma in an Infant With a TP53 Germline Mutation: A Case Report and Literature Review.. J Pediatr Hematol Oncol. 2019. PMID: 29746440. Local full text: 29746440.md ↩ ↩2 ↩3

  7. Adrenocortical tumors, primary pigmented adrenocortical disease (PPNAD)/Carney complex, and other bilateral hyperplasias: the NIH studies.. Horm Metab Res. 2007. PMID: 17578766. Local full text: 17578766.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  8. [Diagnosis and treatment of primary pigmented nodular adrenocortical disease report of 4 cases].. Zhonghua Yi Xue Za Zhi. 2009. PMID: 20058620. Local full text: 20058620.md ↩ ↩2 ↩3

  9. Bilateral and recurrent adrenocortical carcinoma in MEN1: a case report and review of the literature.. Endocr Oncol. 2025. PMID: 41141223. Local full text: 41141223.md ↩ ↩2 ↩3 ↩4 ↩5

  10. Adrenocortical neoplasms in children: radiologic-pathologic correlation.. Radiographics. 1999. PMID: 10464805. Local full text: 10464805.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8

  11. Adrenocortical tumors in children.. Braz J Med Biol Res. 2000. PMID: 11004724. Local full text: 11004724.md ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  12. Pediatric adrenocortical carcinoma.. Front Endocrinol (Lausanne). 2022. PMID: 36387865. Local full text: 36387865.md ↩ ↩2 ↩3 ↩4 ↩5

  13. Adrenocortical carcinoma: Pediatric aspects (Review).. Exp Ther Med. 2022. PMID: 35317446. Local full text: 35317446.md ↩ ↩2 ↩3

  14. Imaging of pediatric adrenal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.. Pediatr Blood Cancer. 2023. PMID: 36193741. Local full text: 36193741.md ↩ ↩2

  15. Fetal and newborn adrenocortical tumors.. Fetal Pediatr Pathol. 2010. PMID: 20334485. Local full text: 20334485.md ↩ ↩2 ↩3 ↩4 ↩5

  16. Frequency of the TP53 p.R337H mutation in a Brazilian cohort of pediatric patients with solid tumors.. Mol Biol Rep. 2020. PMID: 32671623. Local full text: 32671623.md ↩ ↩2 ↩3 ↩4

  17. Ovarian thecal metaplasia of the adrenal gland in association with Beckwith-Wiedemann syndrome.. World J Radiol. 2014. PMID: 25550997. Local full text: 25550997.md ↩ ↩2 ↩3

  18. Early detection of adrenocortical carcinoma in a child with Li-Fraumeni syndrome.. Pediatr Blood Cancer. 2009. PMID: 19101993. Local full text: 19101993.md ↩ ↩2 ↩3 ↩4

  19. Intensive Combination Immunotherapy and Neuroinflammation Resolution in a Child With Anti-PCA-1 (Yo) Paraneoplastic Syndrome and 2 Malignancies.. Child Neurol Open. 2018. PMID: 30288393. Local full text: 30288393.md ↩ ↩2

  20. A rare pediatric case of Li-Fraumeni syndrome presenting with virilization symptoms and dual primary malignancies on magnetic resonance imaging and [18F]-fluorodeoxyglucose positron emission tomography/computed tomography.. Pediatr Radiol. 2025. PMID: 40815376. Local full text: 40815376.md ↩ ↩2

  21. ADRENAL CORTICAL CARCINOMA IN INFANCY.. Rev Paul Pediatr. 2019. PMID: 30726455. Local full text: 30726455.md ↩ ↩2

  22. 12-Year-Old Girl Diagnosed With Li-Fraumeni Syndrome and Concomitant Adrenocortical Carcinoma (ACC).. Cureus. 2022. PMID: 36457625. Local full text: 36457625.md ↩ ↩2 ↩3

  23. Prenatal diagnosis of fetal bilateral adrenal carcinoma.. Ultrasound Obstet Gynecol. 2005. PMID: 16254889. Local full text: 16254889.md ↩ ↩2 ↩3

  24. Neonatal Cushing Syndrome: A Rare but Potentially Devastating Disease.. Clin Perinatol. 2018. PMID: 29406000. Local full text: 29406000.md ↩ ↩2 ↩3

  25. Spontaneously regressing adrenocortical carcinoma in a newborn. A case report with DNA ploidy analysis.. Cancer. 1988. PMID: 3390790. Local full text: 3390790.md ↩ ↩2

  26. 68Ga-DOTANOC PET/CT in Multiple Endocrine Neoplasia 1 With Associated Adrenocortical Carcinoma.. Clin Nucl Med. 2022. PMID: 35195585. Local full text: 35195585.md ↩ ↩2

  27. Genetic Dissection of Primary Aldosteronism in a Patient With MEN1 and Ipsilateral Adrenocortical Carcinoma and Adenoma.. J Clin Endocrinol Metab. 2022. PMID: 36179244. Local full text: 36179244.md ↩ ↩2 ↩3

  28. Adrenocortical cancer in Carney complex: a paradigm of endocrine tumor progression or an association of genetic predisposing factors?. J Clin Endocrinol Metab. 2012. PMID: 22312093. Local full text: 22312093.md ↩ ↩2 ↩3

  29. [Primary pigmented nodular adrenocortical dysplasia. A rare cause of Cushing’s syndrome].. Dtsch Med Wochenschr. 1996. PMID: 8964212. Local full text: 8964212.md ↩ ↩2 ↩3

  30. Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing’s syndrome.. Eur J Endocrinol. 2013. PMID: 23065993. Local full text: 23065993.md ↩ ↩2

  31. In-depth Genetic and Molecular Characterization of Unilateral Coexisting Adrenal Cortical Adenoma and Carcinoma in the Context of MEN1 Syndrome.. Endocr Pathol. 2026. PMID: 41806143. Local full text: 41806143.md ↩ ↩2

  32. Fatal extraintestinal adrenal malignancy in a 12-year-old girl with familial adenomatous polyposis.. J Pediatr Gastroenterol Nutr. 2014. PMID: 23575299. Local full text: 23575299.md ↩ ↩2

  33. Isolated clinical syndrome of primary aldosteronism in a patient with adrenocortical carcinoma. Case report and review of the literature.. Urol Int. 1995. PMID: 8588274. Local full text: 8588274.md ↩ ↩2

  34. Clinicopathologic Correlates of Primary Aldosteronism.. Arch Pathol Lab Med. 2015. PMID: 26125435. Local full text: 26125435.md ↩ ↩2

  35. Aldosterone-Producing Adrenocortical Carcinoma with Co-Secretion of Cortisol and Estradiol: A Case Report.. J ASEAN Fed Endocr Soc. 2018. PMID: 33442112. Local full text: 33442112.md ↩ ↩2

  36. Malignant adrenal tumors.. Semin Pediatr Surg. 2006. PMID: 16458846. Local full text: 16458846.md ↩ ↩2

  37. Gene expression profiling of childhood adrenocortical tumors.. Cancer Res. 2007. PMID: 17234769. Local full text: 17234769.md ↩ ↩2

  38. Isolated primary aldosteronism in a patient with adrenal carcinoma and XY/XXY mosaic Klinefelter’s syndrome.. J Urol. 1990. PMID: 2231941. Local full text: 2231941.md ↩

  39. Adrenocortical carcinoma with primary aldosteronism associated with Cushing syndrome during recurrence.. BJU Int. 2002. PMID: 12460368. Local full text: 12460368.md ↩

  40. Secondary hypertension in pregnancy due to an adrenocortical carcinoma.. Aust N Z J Obstet Gynaecol. 2004. PMID: 15387874. Local full text: 15387874.md ↩

  41. Pediatric adrenal cortical carcinoma: brain metastases and relationship to NF-1, case reports and review of the literature.. J Neurooncol. 2005. PMID: 16132517. Local full text: 16132517.md ↩

  42. A rare case of an aldosterone secreting metastatic adrenocortical carcinoma and papillary thyroid carcinoma in a 31-year-old male.. Rare Tumors. 2011. PMID: 22355500. Local full text: 22355500.md ↩

  43. Laparoscopic treatment of Cushing’s syndrome in a woman in late pregnancy - a case presentation.. Wideochir Inne Tech Maloinwazyjne. 2011. PMID: 23255991. Local full text: 23255991.md ↩

  44. Adrenocortical carcinoma in pregnancy: A diagnostic dilemma.. Indian J Urol. 2014. PMID: 25097324. Local full text: 25097324.md ↩

  45. Adrenal cortical carcinoma mimicking early severe preeclampsia.. Obstet Med. 2014. PMID: 27512421. Local full text: 27512421.md ↩

  46. Ectopic adrenocortical carcinoma located in the ovary.. Eur J Endocrinol. 2016. PMID: 27523914. Local full text: 27523914.md ↩

  47. Network analysis reveals potential markers for pediatric adrenocortical carcinoma.. Onco Targets Ther. 2016. PMID: 27555782. Local full text: 27555782.md ↩

  48. Adrenocortical carcinoma characterized by gynecomastia: A case report.. Clin Pediatr Endocrinol. 2018. PMID: 29403152. Local full text: 29403152.md ↩

  49. Pediatric adrenocortical carcinoma complicated by uric acid nephrolithiasis: a unique case report.. BMC Urol. 2025. PMID: 40307791. Local full text: 40307791.md ↩

  50. Bilateral adrenal tumors presenting with Cushing syndrome in the setting of horseshoe kidney: surgical and urological considerations (case report).. Pan Afr Med J. 2025. PMID: 41393183. Local full text: 41393183.md ↩

  51. Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I.. Am J Surg Pathol. 1997. PMID: 9298884. Local full text: 9298884.md ↩

  52. C-cell carcinoma (medullary thyroid carcinoma) associated with multiple endocrine neoplasms in a ferret (Mustela putorius).. Vet Pathol. 2000. PMID: 10810995. Local full text: 10810995.md ↩

  53. A dog pedigree with familial medullary thyroid cancer.. Int J Oncol. 2006. PMID: 17016649. Local full text: 17016649.md ↩

  54. MicroRNA-142-3p, a novel target of tumor suppressor menin, inhibits osteosarcoma cell proliferation by down-regulation of FASN.. Tumour Biol. 2014. PMID: 25034529. Local full text: 25034529.md ↩

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