Introduction
Endocrine tumor syndromes constitute a group of disorders characterized by tumors in hormone-producing tissue. These conditions mainly affect younger patients and often exhibit familial inheritance patterns, with sporadic cases being less common. Patients often initially present with signs and symptoms indicative of hormone overproduction. Nonetheless, non-functional tumors may become apparent due to their mass effect. Pathogenic germline mutations in tumor suppressor genes and oncogenes are implicated in the emergence of various hereditary endocrine tumor syndromes. However, pediatric cases within families may exhibit only subtle clinical signs and minor biochemical alterations, leading to potential misdiagnosis during clinical evaluations.
Over the past few decades, advances in molecular genetics have made it possible to identify many genes associated with the development of endocrine tumors in children. This has improved our understanding of the disease mechanisms, enabling an early diagnosis, timely tumor surveillance, and improved treatment strategies. This review aims to describe the clinical manifestations and molecular genetic basis of endocrine cancer syndromes, focusing on those of adrenal origin.
Ethics statement
It is a literature database-based review; therefore, neither approval by the institutional review board nor obtainment of informed consent was required.
Adrenocortical tumors
Adrenal tumors are classified into those of the adrenal cortex and those of the adrenal medulla and extra-adrenal paraganglia, according to the World Health Organization (WHO) classification of endocrine tumors [1]. Adrenocortical tumors are found in approximately 5% of the general population, with the majority being small, benign, non-functioning adrenocortical adenomas [2,3]. Adrenocortical carcinomas, however, are rare, with an incidence of 0.2 to 0.3 cases per million in adults [2,3]. Most adrenocortical tumors in adults are discovered incidentally, without excess adrenal hormone production, although 15% are functioning tumors [2]. In contrast, in the pediatric population, adrenal hormone excess is observed in about 80% to 90% of patients, with two age peaks: the first 5 years of life and adolescence [4,5]. In pediatric cases, androgen excess is the commonly observed presentation, followed by Cushing syndrome or a combination of both [4]. Therefore, it is important to consider multiple possibilities in the differential diagnosis of virilization, including androgen-secreting tumors and congenital adrenal hyperplasia [6,7]. Cushing syndrome tends to be more prevalent in older age groups [4]. Androgen excess is associated with accelerated growth, whereas cortical excess leads to a reduction in growth velocity. Therefore, clinical suspicion of adrenal tumors is warranted when patients present with symptoms of virilization and Cushing syndrome. Notably, adrenocortical carcinomas are more common in pediatric cases than in adults [8,9]. Furthermore, some cases of adrenocortical carcinomas are linked to various familial cancer syndromes, such as Beckwith-Wiedemann syndrome (BWS), Li-Fraumeni syndrome (LFS), and multiple endocrine neoplasia type 1 (MEN1) [4,10]. Untreated or inadequately treated congenital adrenal hyperplasia can also lead to the development of adrenal tumors [11,12]. Therefore, when diagnosing adrenocortical carcinoma in pediatric patients, the possibility of familial cancer syndromes must be considered. These syndromes increase the risk of other tumors and require a comprehensive management approach. Thus, a thorough differential diagnosis is essential to ensure appropriate and effective treatment strategies.
Li–Fraumeni syndrome
LFS is a hereditary cancer syndrome caused by a pathogenic mutation in the TP53 gene. This condition is associated with a high risk of developing various childhood and adult-onset tumors, including adrenocortical carcinomas, breast cancer, soft tissue sarcomas, osteosarcomas, leukemia, and brain tumors [13,14]. The estimated lifetime cancer risk for women with LFS exceeds 90%, while it is over 70% for men [14]. Additionally, individuals with LFS face a 5% to 13% lifetime risk of developing adrenocortical carcinoma [12,15-17]. The incidence of germline TP53 mutations is particularly high in those diagnosed with adrenocortical carcinoma during childhood, with the rate decreasing from 58% in those diagnosed before the age of 12% to 25% in those diagnosed between the ages of 12 and 20 [15]. The typical clinical presentation of LFS includes symptoms arising from glucocorticoid and androgen excess in early childhood [12]. The long-term prognosis is closely linked to the age at diagnosis and the stage of the tumor; pediatric patients with completely resected small tumors generally have a favorable prognosis [12,18]. LFS should be considered clinically in individuals who develop a diverse range of cancers at a young age or in those with a family history of cancers such as adrenocortical tumors, breast cancer, or brain tumors. It is important to note that genetic testing for TP53 mutations is strongly recommended for all pediatric cases of adrenocortical tumors, regardless of family history [12,19].
Beckwith-Wiedemann syndrome
BWS is a genomic imprinting disorder characterized by overgrowth and an increased risk of developing various tumors. Individuals with BWS are at a higher risk for embryonic tumors, such as Wilms' tumor, hepatoblastoma, and neuroblastoma. IGF2 plays a significant role in the fetal development of the adrenal gland and steroidogenesis, and overexpression of IGF2 has been observed in pediatric patients with adrenocortical tumors [20,21]. While adrenal hyperplasia and adrenal tumors can occur in BWS, they are less common than embryonic tumors. The overall tumor risk associated with BWS is approximately 5%–10%, with adrenocortical carcinoma accounting for about 7% of malignancies [22]. The incidence of adrenocortical carcinoma in patients with BWS is less than 1%. The most common adrenal masses reported in the literature are incidentally diagnosed adrenal cysts during prenatal and postnatal ultrasound screening [23]. There have also been cases of patients diagnosed with adrenal adenomas due to virilization and cortisol excess. Additionally, a few reports exist of patients with BWS and adrenocortical carcinoma presenting with Cushing's syndrome and virilization [23,24]. For patients with BWS, screening for adrenal tumors is recommended, including clinical evaluations for hormone excess, adrenal ultrasound, and monitoring serum dihydroepiandrosterone sulfate levels every 4 to 6 months [25]. However, given the relatively low incidence of adrenal tumors in BWS, there is limited data on the effectiveness of these screening methods [25].
Multiple endocrine neoplasia type 1 and 4
MEN1 is a rare hereditary cancer syndrome characterized by endocrine and extra-endocrine tumors, including parathyroid hyperplasia/adenoma, pituitary adenoma, and gastrointestinal neuroendocrine tumors. Heterozygous mutations in the MEN1 tumor suppressor gene are identified in 80% to 90% of MEN1 cases [26]. Adrenal involvement is present in 10% of patients, and 1.4% of MEN1 cases develop adrenocortical carcinoma [27]. In approximately 6% of cases, adrenal involvement is the initial manifestation of MEN1 [27,28]. The majority of adrenocortical tumors in this condition are non-functional, although adrenocortical hormone excess is observed in 15% of MEN1 patients. Adrenocortical tumors are rare in the pediatric population [29]. While the incidence of adrenocortical tumors in LFS and BWS is likely to decrease with age, the incidence in MEN1 may increase with age. For adrenal screening in MEN1, abdominal imaging with CT or MRI is recommended every 3 years, and adrenal lesions require ongoing radiologic surveillance for signs of malignancy [30]. Biochemical evaluation is recommended for lesions larger than 1 cm or for those that present with clinical symptoms [30].
MEN4 is a newly identified MEN syndrome with phenotypic characteristics similar to MEN1. It is caused by mutations in the CDKN1B gene. The prevalence of CDKN1B mutations in patients presenting with neoplasia related to MEN1 is estimated to be approximately 2%−3% [31,32]. However, due to the limited number of reported cases and the likelihood of undiagnosed cases, the exact incidence and prevalence of MEN4 remain unclear. Additionally, there have been reports of adrenal tumors associated with MEN4, including two patients who presented with non-functioning adrenal masses [31,32].
Bilateral macronodular and micronodular adrenal cortical disease
The understanding of germline susceptibility and the clonal-neoplastic nature of adrenocortical nodules has led to the refinement of their classification into three categories: sporadic nodular adrenocortical disease, bilateral micronodular adrenocortical disease, and bilateral macronodular adrenocortical disease (BMAD) [33]. Sporadic nodular adrenocortical disease typically presents as non-functioning and can involve one or both adrenal glands. In contrast, bilateral micronodular and macronodular adrenocortical diseases usually result in hypercortisolism and affect both adrenal glands [33]. These latter conditions are often associated with germline mutations. BMAD is characterized by adrenal nodules that are 1 cm or larger and commonly leads to Cushing syndrome, predominantly occurring in adults. The growth of adrenal nodules is related to the activation of the cAMP/protein kinase A (PKA) pathway. Activating mutations in MC2R and GNAS stimulate downstream cAMP/PKA signaling, leading to the development of BMAD [34]. Pathogenic mutations in ARMC5, a tumor suppressor gene, have been implicated in familial and sporadic cases of BMAD [35]. Additionally, research has revealed that BMAD is caused by a two-step genetic process in ARMC5: an inherited mutation, followed by a somatic second-hit mutation [35,36]. In addition, germline mutations in MEN1, FH, and APC have also been reported in this condition [37]. The typical age of diagnosis is usually between 40 and 60 years, and the condition is rare in children [35-37].
Micronodular adrenal cortical disease is characterized by the presence of multiple small adrenocortical nodules (<1 cm). It is subdivided into isolated micronodular adrenal cortical disease (i-MAD) and primary pigmented micronodular adrenal cortical disease (PPNAD). Carney complex is characterized by the pigmented lesions on the skin and/or mucosa, PPNAD, cardiac myxomas, and both benign and malignant endocrine tumors [38]. Irrespectively of the subtype, this disease is associated with germline mutations in PRKAR1A and PRKACA [39]. PRKAR1A encodes the type 1A regulatory subunit of PKA, and inactivating mutations in this gene lead to PKA dysregulation and are associated with PPNAD and other forms of adrenal cortical disease [38]. PRKACA encodes the catalytic isoform of PKA, and genetic defects in PRKACA constitutively activate PKA, resulting in cortisol-producing tumors [39]. In recent reports, mutations in PDE11A and PDE8B have been identified in patients with i-MAD [40,41]. Given the relative rarity of Cushing syndrome in children, careful consideration of the differential diagnosis, especially regarding bilateral MAD [12,42], is of paramount importance when these symptoms emerge during childhood.
Tumors of the adrenal medulla and paraganglia
Pheochromocytomas (PHEOs) are tumors that secrete catecholamines and originate from chromaffin cells in the adrenal medulla. They account for 80%−85% of all catecholamine-secreting tumors, while the remaining 10%−15% are paragangliomas (PGLs), which occur outside the adrenal glands [43]. These conditions are uncommon causes of hypertension, affecting 0.5%−2% of pediatric cases, and they typically manifest in the first decade of life [12,44-46]. Hypertension is noted in 80%−90% of affected pediatric patients and is often accompanied by symptoms such as palpitations, headaches, or sweating [12,44-46]. Historically, the "rule of 10" posited that only 10% of cases were hereditary, malignant, extra-adrenal, and bilateral. However, recent data from the European-American Pheochromocytoma-Paraganglioma Registry (EAPPR) indicate a much higher incidence of hereditary cases among pediatric patients, with 80% of 164 pediatric patients having a germline mutation [44]. This represents a significant increase from the previously estimated 30%−40% in smaller case series [45,47,48], a change attributed to enhanced mutation screening, the identification of novel mutations, and more comprehensive population-based data from registries such as the EAPPR. These tumors are associated with hereditary cancer syndromes such as MEN2, neurofibromatosis type 1 (NF1), and von Hippel-Lindau (VHL) disease [43,49]. Germline mutations in the SDHx genes are frequently identified in these conditions [43]. These syndromes are inherited in an autosomal dominant pattern with variable penetrance.
Genetic testing for VHL and MEN2 is often recommended for patients diagnosed with PHEO or PGL, especially when there is an early onset or a family history of related tumors [50,51]. The presence of bilateral or multifocal PHEOs strongly suggests these hereditary syndromes. Clinical features such as retinal hemangioblastomas or clear cell renal carcinoma may point to VHL [43,50], whereas medullary thyroid cancer (MTC) or primary hyperparathyroidism might be indicative of MEN2 [52,53]. Malignant or atypical presentations are additional indications for genetic testing. This approach is essential as it informs not only the management of the current tumor but also the monitoring for other neoplasms associated with these syndromes.
Von Hippel-Lindau syndrome
VHL disease is an autosomal dominant tumor syndrome that occurs in approximately 1 in 36,000 live births [54]. It results from germline mutations in the VHL gene, a tumor suppressor gene that regulates blood vessel formation through the hypoxia-inducible factor [54]. Individuals with this condition are predisposed to developing highly vascularized tumors in multiple organs, including hemangioblastomas of the retina, cerebellum, and spine, renal cell carcinoma, PHEO, PGL, pancreatic cysts, and neuroendocrine tumors [54]. VHL is classified into type 1 and type 2 disease based on genotype-phenotype correlations, with PHEO associated with type 2 VHL in 25%−30% of cases [55]. PHEO in VHL typically presents in the second decade of life [54]. In children, PHEO and PGL may be the initial indicators of VHL, with cases reported in individuals as young as 5 years old [50]. VHL-associated PHEO has a high incidence of bilateral lesions in up to 60% of cases and synchronous or metachronous recurrence in 10%−30% [51]. These findings underscore the significant incidence of PHEO and PGL in patients with VHL and highlight the necessity for early and lifelong screening. In addition to abdominal imaging, annual testing of plasma metanephrines and plasma normetanephrines is recommended starting at the age of 5 [56].
Multiple endocrine neoplasia type 2
MEN2A is characterized by MTC, PHEO, and primary hyperparathyroidism, which affect 70%–80% of individuals with MEN2. The RET proto-oncogene plays a role in both MEN2 and sporadic or familial MTC. MTC is the most common manifestation in patients with MEN2A, presenting as early as the first 5 years of life. A smaller proportion of patients develop PHEO, with the likelihood varying based on specific RET mutations. Mutations in RET codon 634 are highly penetrant for PHEO, with the risk increasing from 25% at 30 years of age to 88% by 77 years of age [57]. PHEOs in patients with MEN2A are predominantly benign, multicentric, and bilateral [53]. Furthermore, in cases where a unilateral PHEO develops, there is a 30%–50% chance of a contralateral PHEO occurring within 10 years [58,59]. Patients with MEN2B almost invariably present with C-cell hyperplasia and MTC, and PHEO occurs in 30%–50% of cases. They also exhibit distinctive features such as mucosal neuromas, intestinal ganglioneuromatosis, hyperflexible joints, and a Marfanoid body habitus [53]. Screening for PHEO in children is recommended to start at age 11 for those in the high and highest risk categories, and at age 16 for those in the moderate risk category. PHEO in MEN2 typically progresses, with up to 50% of cases developing bilateral lesions and 25% developing a metachronous lesion within 5–10 years [60,61]. The highly variable interval between the first and second PHEO, along with the lack of a direct correlation with the RET mutation, necessitates prolonged follow-up.
Neurofibromatosis type 1
NF1 is a multisystem genetic disorder that predisposes individuals to benign and malignant tumors due to mutations in the NF1 gene [62]. This gene is responsible for producing neurofibromin, a protein that acts as a negative regulator of Ras activity [63]. When neurofibromin is lost, there is an increase in mitogenic signaling, leading to enhanced cellular proliferation or differentiation [63]. PHEOs in NF1 patients are reported in approximately 0.1%−3% of cases, with an average age of onset at 40 years; however, a prospective study has indicated a much higher prevalence of 14.6% [64,65]. The reason for this discrepancy may be the previous lack of biochemical testing, which suggests that some cases may have gone undetected. About half of the cases of PHEOs and PGLs are symptomatic [66]. Biochemical testing for these conditions, which includes measuring urine or plasma catecholamines and metanephrines, is recommended when symptoms are suggestive, during pregnancy, and before elective surgery involving general anesthesia [62]. However, routine biochemical screening for PHEOs and PGLs in adults with NF1 is not currently advised [62]. In a recent notable case, a dopamine-secreting PHEO was discovered in a 13-year-old patient with NF1 [67]. This particular tumor did not exhibit the classic symptoms of PHEO, nor were there elevated levels of metanephrines. Consequently, the physician's clinical suspicion was pivotal in the differential diagnosis of adrenal tumors, particularly in light of the patient's predisposition to cancer.
Succinate dehydrogenase-related pheochromocytomas and paragangliomas
Succinate dehydrogenase (SDH), also known as mitochondrial complex II, is a crucial enzyme for mitochondrial energy production. It is anchored to the inner mitochondrial membrane and consists of four distinct subunits: A, B, C, and D [68]. While the loss of function in SDHB, SDHC, and SDHD is strongly associated with the development of PHEO and PGL, data on SDHA are more limited [69]. Approximately 20% of patients diagnosed with PHEO or PGL carry a germline mutation in one of the SDHx genes [69,70]. Individuals with SDHD mutations exhibit high penetrance, often developing multiple tumors, predominantly in the parasympathetic region of the head and neck [68,69]. In contrast, SDHB mutations predispose carriers primarily to retroperitoneal PHEO and sympathetic PGL, and are associated with a more aggressive disease course, including a higher rate of malignancy and metastasis [68,69]. Data on SDHC mutations are scarce, but carriers typically present with non-metastatic head and neck PGLs [69]. For asymptomatic carriers of SDHB mutations, initial tumor screening is recommended between the ages of 6 and 10 years. For those with asymptomatic SDHA, SDHC, and SDHD mutations, screening should commence between the ages of 10 and 15 years [69]. In children, biochemical measurements are utilized for screening. Additionally, MRI of the head, neck, chest, abdomen, and pelvis is the recommended primary imaging modality for initial tumor screening in childhood [69].
Conclusion
Over the past 20 years, significant progress has been made in understanding the syndromes that lead to endocrine tumors, greatly improving the diagnostic and therapeutic approaches available to clinicians. These advances include the identification of key genes responsible for these tumors and the elucidation of the pathways that lead to endocrine cell hyperplasia and tumor progression. Nonetheless, challenges remain in pinpointing specific genes and determining their exact role in initiating these tumors. Alongside these genetic insights, this review has effectively outlined the incidence and clinical presentation of adrenal tumors (Table 1). This in-depth knowledge is crucial for improving patient care by facilitating early detection, guiding effective management, and informing the development of targeted treatment strategies.
