Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: clinical features, genetics and surveillance recommendations in childhood

Abstract

Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the Multiple Endocrine Neoplasia (MEN) syndromes, including MEN1, MEN2A and B, MEN4, and Hyperparathyroid-Jaw Tumor (HPT-JT) Syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT Syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome.

Introduction

Tumors of hormone-producing tissues are common among patients with hereditary cancer syndromes. Signs and symptoms of hormone excess are the frequent initial findings among patients with endocrine tumors, although mass-effect may be the presenting complaint, particularly in the case of non-functional tumors. Pathogenic germline variants in different tumor suppressor genes and oncogenes are responsible for distinct hereditary endocrine tumor syndromes. Each of the so-called Multiple Endocrine Neoplasia (MEN) syndromes is characterized by a distinct spectrum of clinical manifestations, both benign and malignant with unique underlying genetic predisposition. The focus of this article is the pre-symptomatic screening of at-risk patients which has allowed for earlier detection and intervention, with a resultant decrease in mortality and morbidity associated with these tumors.

Expert or consensus guidelines currently exist for many of the clinical entities described herein. In the course of reviewing existing guidelines, effort was made to balance the financial, personal and psychosocial burdens of surveillance with the benefits of early detection and intervention with respect to consequences of hormonal hypersecretion. This was particularly pertinent among those histologically benign neoplasms, where morbidity is primarily paraneoplastic. Experiences with other hereditary tumor syndromes has also demonstrated reduced surgical morbidity when tumors are identified at earlier stages as the result of pre-symptomatic surveillance(1). It is also recognized that patient preference plays an important role in determining the onset of early tumor surveillance and intervention wherein data regarding optimal timing are imprecise. Such patient preferences should be ascertained and implemented by the clinical team, wherever medically appropriate.

Multiple Endocrine Neoplasia Type 1 (MEN1)

Multiple Endocrine Neoplasia Type 1 (MEN1, OMIM 131100) was initially identified as early as 1903 (2), and formally defined by Underhal and Werner nearly 50 years later (3,4) as an autosomal-dominant familial disorder characterized by 1) primary hyperparathyroidism (PHPT) and hypercalcemia resulting from parathyroid adenomas (generally multi-glandular); 2) hormone-secreting or non-secreting pancreatic islet tumors (commonly gastrinomas and rarely insulinomas, VIPomas, glucagonomas or other neoplasms); and 3) anterior pituitary neuroendocrine tumors (PitNETs), predominantly prolactinomas, less frequently, growth hormone secreting adenomas (5,6) and rarely, other PitNETs (which constitute <5% of pituitary tumors in MEN1)(7). Angiofibromas, lipomas and collagenomas (8–10) are common dermatologic manifestations of MEN1, and adrenocortical adenomas are identified in 35% of patients with MEN1 (11). Other minor manifestations of MEN1 include leiomyomas (12) and CNS neoplasms (including ependymomas and meningiomas) (13,14). The prevalence of MEN1 has been estimated at 1:20,000–40,000(15,16). Pedigrees expressing PHPT in the absence of other MEN1 manifestations (familial isolated hyperparathyroidism, FIHP) have also been described and may simply reflect PHPT as the most penetrant manifestation of MEN1 (17). Although originally thought to be an adult-onset disorder, tumors have been diagnosed as young as age five years (18) and continue to manifest through older adulthood. Seventeen percent of MEN1-associated tumors are diagnosed under the age of 21 years (19). Recent data suggest that 42% of MEN1 patients in the second decade of life may possess clinically occult (non-functioning) pancreatic NETs(20). Disease penetrance for a first manifestation of MEN1 among MEN1 carriers is estimated at 45%, 82% and 96% at 30, 50 and 70 years (21).

Although MEN1 may present with any of its major constituent manifestations, PHPT is the most common presenting feature and manifests in 95% of MEN1 patients (5,7). Pancreatic neuroendocrine tumors occur in 40–75% of MEN1 patients (7,20), whereas PitNETs are identified in 30–55% (22,23). Most commonly, these PitNETs are microadenomas <1cm, but they may be larger and retain potential to compromise visual fields. Clinical diagnosis of MEN1 is predicated on the identification of at least two of the major constituent tumors (e.g., parathyroid tumor, pancreatic islet cell tumor, PitNET ). Specific indications for genetic testing are articulated below. Patients with MEN 1 are at increased risk of premature death (24,25) with malignant pancreatic neuroendocrine tumors (including non-functioning tumours) the leading cause of death (19,20,26), although a secular trend has suggested decreasing mortality over the past 20 years, presumably the result of more prevalent screening for pre-symptomatic abdominal tumors (19).

Molecular Genetics of MEN1

MEN1 is associated with pathogenic variants in the MEN1 tumor-suppressor gene on 11q13, which encodes the Menin protein, a scaffold protein with suspected functions including cell-cycle control, transcriptional regulation and maintenance of genomic stability (27,28). Inactivating pathogenic variants in MEN1 in affected individuals occur throughout the gene and include truncation, missense, splice-site, and insertions/deletions (29). A limited number of large deletions also have been observed. Pathogenic germline variants in MEN1 are identified in 80–95% of familial cases (7,30) and 65–70% of de novo cases (31). Individuals meeting clinical diagnostic criteria for MEN1 without an identifiable pathogenic gene variant tend to develop tumors at an older age. This may, in fact, reflect carriers of other pathogenic gene variants such as CDKN1B (see MEN4, below), although these are rare (32). There are no apparent genotype-phenotype correlations in MEN1, and no mutational hotspots.

Comprehensive MEN1 genetic testing is indicated in 1) any person with two or more constituent MEN1 tumors; 2) any person with one MEN1 tumor and a first-degree relative with MEN1; or 3) any individual under the age of 30 with PHPT, pancreatic precursor lesions (33) or pancreatic islet tumor, regardless of family history. The prevalence of pathogenic MEN1 variants among individuals with isolated PitNETs is much lower (in some series 0–5%(34,35)) and in patients <30 years, the prevalence of pathogenic MEN1 variants may be as low as 3.4%(36). Thus, the role for genetic screening of MEN1 in patients with isolated PitNET is less clear(37).

In addition, genetic testing of the specific MEN1 pathogenic variant identified in the proband (familial mutation testing) should be offered to all at risk first-degree relatives. Finally, suspicion for “atypical” MEN1 has been proposed as an indication for testing, and comprises any of: parathyroid adenoma prior to age 45, gastrinoma (at any age), multiple pancreatic NETs, or either multiglandular/recurrent parathyroid adenomas or four-gland parathyroid hyperplasia (38).

Pre-symptomatic Surveillance for MEN1 manifestations

Recommendations for pre-symptomatic screening in MEN1 carriers have been established and are based on the youngest age at which disease manifestations have been reported (5,7,21)Table 1 defines a recommended surveillance paradigm, modified from that described by Thakker et al. (5). Delays in diagnosis and/or the onset of tumor surveillance among MEN1-carriers are associated with increases in both morbidity and mortality (39). For first-degree relatives of MEN1 carriers with unknown mutational status, we advocate annual serum prolactin from age five and annual serum calcium (corrected for albumin) from age 10 years. While treatment approaches for most manifestations of MEN1 are beyond the scope of this report, approaches to treatment of PHPT are addressed below.

Table 1.

Surveillance for MEN1 mutation carriers

MEN1 manifestation	Screen Starting at Age	Clinical Screening	Annual Biochemical Tests	Imaging
Insulinoma	5 yrs	Syncope, light-headedness, documented hypoglycemia, ⇑growth	Fasting Glucose & Insulin	None
Pituitary neuroendocrine tumor	5 yrs+	Headaches, visual changes, galactorrhea, ⇑growth	Prolactin, IGF-1	Brain MRI (q3 years)
Parathyroid Adenoma/ 1o HyperPTH	8 yrs	Back pain, bone pain, weakness, fatigue, psychiatric changes, kidney stones, nausea, vomiting, constipation. Multiple or pathologic fractures.	Calcium++	None
Pancreatic NET	10 yrs	Generally not identified symptomatically. VIPoma can cause profuse diarrhea. Glucagonoma assoc. with hyperglycemia, nausea, polyuria, thirst.	(Chromogranin A, glucagon, proinsulin, pancreatic polypeptide, VIP)+++	Abdominal MRI (annually)
Adrenal adenoma	10 yrs	None	None	MRI (contemporaneous with pancreatic imaging)
Gastrointestinal, Bronchial and Thymic NETs	20 yrs	Frequently asymptomatic, but h/o flushing, diarrhea, wheezing, edema or abdominal pain should arouse suspicion		CT/MRI Chest and Abdomen (q1–2 years)
Gastrinoma (duodenal and pancreatic)	20 yrs	Abdominal pain, gastric ulcers. Proton-pump inhibitor usage.	Fasting Gastrin	None

⁺MRI surveillance is to begin once patient is able to tolerate a non-sedated MRI. In the authors’ experience, this is generally at about the age of 5 years, but may be deferred on an individualized basis.

⁺⁺Hypercalcemia on screening should prompt assessment with contemporaneous serum calcium and iPTH to establish a diagnosis of PHPT.

⁺⁺⁺Pancreatic tumours may be non-secretory, therefore the added sensitivity contributed by biochemical screening has not been demonstrated.

(Data from Thakker et al. Ref: (5))

Multiple Endocrine Neoplasia 2A, 2B and Familial Medullary Thyroid Carcinoma

Multiple endocrine neoplasia type 2 (MEN2) was initially described by Sipple in 1961 (40). It results from pathogenic germline variants in the RET proto-oncogene. MEN2 is characterized by risk for both medullary thyroid carcinoma (MTC) and pheochromocytoma (PHEO) and can be further subdivided, clinically and genetically, into MEN2A (OMIM 171400) and MEN2B (OMIM 162300). MEN2A can also manifest PHPT, whereas MEN2B has earlier onset of tumors and may present with mucosal neuromas, intestinal ganglioneuromatosis and characteristic physical features. The prevalence of MEN2 is estimated at 1:35,000 to 1:40,000 (41). Familial medullary thyroid carcinoma (FMTC), once considered a separate subtype from MEN2A, is now widely considered to be a variant of MEN2A with decreased penetrance of PHEO and PHPT. MEN2A accounts for 91% of MEN2 patients (35% with isolated FMTC) and MEN2B, the remaining 9%.

MEN2 is inherited in an autosomal dominant fashion. Pathogenic germline RET variants are associated with striking genotype-phenotype correlations and the clinical phenotype has characteristic and predictable features based on the affected codon (Table 2). The risk for developing each of the three pathognomonic tumors in MEN2 is based on the codon-specific variant, with the most penetrant forms [American Thyroid Association (ATA) “Highest” and “High” risk (42)] characterized by lifetime risks of >95% risk to develop MTC, 50% risk to develop PHEO, and, for those with “High” risk alleles, a 20–30% risk to develop PHPT. Of note, carriers of the M918T variant do not develop PHPT. There is a lower prevalence of PHEO (10–50%) among “moderate” risk allele carriers, with risk conferred by the specific allele (42).

Table 2.

Genotype-Phenotype Associations with Specific RET Mutations

ATA MTC Risk Category	RET Codon	MTC	PHEO	PHPT	CLA	HD
Highest (HST)	918	+++	+++	−	−
High (H)	634, 883	+++	+++	+ −	+ −
Moderate (MOD)	All others	+++	+/++	+	+ (only codon 804)	+ (only codons 609, 611, 618, 620)

Abbreviations: American Thyroid Association (ATA) Risk Categories based on RET allele. MTC: medullary thyroid carcinoma; PHEO: pheochromocytoma; PHPT: primary hyperparathyroidism; CLA: cutaneous lichen amyloidosis; HD: Hirschsprung’s Disease.

Data from Wells et al. (66)

The age of onset of MTC also varies by genotype, occurring in early childhood in those with MEN2B, and adolescence or early adulthood in MEN2A, whereas pedigrees with isolated MTC tend to present with disease onset in middle-age. This difference in age of onset is very relevant clinically with regard to surveillance and surgery recommendations (below). Typically, PHEO presents in the 4^th or 5^th decade of life in pathogenic RET variant carriers, but it has been described in carriers as young as 8 years of age (43). MEN2A can be further classified into “classical MEN2A”, MEN2A with cutaneous lichen amyloidosis (CLA), and MEN2A with Hirschsprung disease (HD).

MEN2B is characterized by a 100% risk of developing MTC (which often presents in infancy and can be more aggressive) and a 50% risk for PHEO. PHPT does not occur in MEN2B. Roughly 50% of MEN2B occurs de novo (44), and presence of common clinical features, including alacrima, mucosal neuromas, constipation (secondary to intestinal ganglioneuromatosis) and marfanoid habitus should raise suspicion for MEN2B (44–46). Early diagnosis and treatment within the first year of life, by a high-volume thyroid surgeon, is critical to increase the potential for surgical prevention or curative treatment of MEN2B-associated MTC (47).

PHEO is associated with both MEN2A and MEN2B, presenting in ~10–50% of pathogenic RET-variant carriers, depending on genotype (42,48). Familial PHEO may also be reflective of pathogenic germline variants at other loci including VHL (von Hippel-Lindau disease), NF1 (Neurofibromatosis type 1/von Recklinghausen disease), SDHx (A-D), TMEM127 or MAX (hereditary PHEO/paraganglioma syndrome) (all described in detail elsewhere in this issue) (49).

Molecular Genetics of MEN2A, 2B and FMTC

The RET proto-oncogene is a receptor tyrosine kinase on 10q11.21, and pathogenic variants have been reported in exons 5, 8, 10, 11, 13, 14, 15 and 16 (with variants in exons 10 and 11 comprising 95% of individuals with MEN2A). The RET protein has an extracellular binding domain, a trans-membrane domain, and an intracellular segment with a split tyrosine kinase domain (50). Variants that strongly activate the intracellular tyrosine kinase domain are associated with early age of onset and more aggressive disease progression. The p.M918T variant in exon 16 disrupts the tyrosine kinase domain. It is considered to be the highest risk variant in the RET gene and is associated with the majority of cases of MEN2B. It is also the most common somatic pathogenic variant occurring in sporadic MTC (51). The p.A883F variant has rarely been reported in individuals with phenotypic features associated with MEN2B, including mucosal neuromas and PHEO (42). MTC presentation in these rare patients has ranged from metastatic disease in early adolescence to later onset and less aggressive disease (52,53). Similarly, specific double-variants in RET occurring on the same allele result in an atypical form of MEN2B with onset around 20–30 years of age (42,54–57). Codon 634 variants are associated with higher risks of PHEO and PHPT than other RET variants (58–60). Variants in codon 634 and 804 are associated with CLA (42,61). MEN2A with HD only occurs in patients with variants in codons 609, 611, 618, 620 (62,63). Lastly, rare patients can be found with combined, heterozygous variants involving A883F, but these occurrences are presently too uncommon to define a predictable phenotype. The de novo mutation rate in MEN2A has been estimated at 9% (64), while that of MEN2B is as high as 50%(44).

Pre-symptomatic Surveillance for MEN2A and MEN2B and Treatment Strategies

Medullary Thyroid Cancer

Routine surveillance for MTC comprises both serial ultrasounds and biochemical monitoring of serum calcitonin levels. Total thyroidectomy, when performed by surgeons experienced in the MEN2 syndromes, is the primary preventive strategy for managing the risk for MTC in individuals with pathogenic RET variants, and it has been shown to be effective in preventing subsequent biochemical evidence of disease (65). However, genotype and calcitonin levels may also allow the clinician to tailor the age at which thyroidectomy is indicated (Figure 1) (66). For the “highest” risk allele, p.M918T, thyroidectomy is advised within the first year of life (42). MTC is preceded by C-cell hyperplasia and hypercalcitoninemia, however, physiological calcitonin levels in infancy may be as high as 50 pg/ml with a decreasing trend over the first three years of life, limiting the utility of this marker to gauge disease status pre-operatively in this age group (67,68). Since the variant arises de novo in approximately 50% of those with p.M918T, these affected individuals are unlikely to have been diagnosed as carriers and typically present with metastatic disease if diagnosis occurs after 5 years of age. Once MTC has metastasized, there is low likelihood of achieving surgical cure. Thus, prophylactic thyroidectomy is standard-of-care whenever achievable (69). Preoperative staging with ultrasound or cross-sectional imaging (e.g., contrast-enhanced neck CT or MRI) is essential to identify regional lymphadenopathy and to facilitate adequate surgical planning. For those with progressive or symptomatic metastatic MTC, two drugs, cabozatanib and vandetinib, have been approved in adults, although neither has been demonstrated to impact survival (70).

Figure 1. Management of patients with a pathogenic RET germline variant detected on genetic screening.

ATA, American Thyroid Association risk categories for aggressive medullary thyroid carcinoma (MTC) (HST, highest risk, H, high risk, MOD, moderate risk); Ctn, calcitonin; CEA, carcinoembryonic antigen; HPTH, hyperparathyroidism; PHEO, pheochromocytoma; RET, REarranged during Transfection; TTX, total thyroidectomy; US, ultrasound. (Reprinted with permission from Wells et al. (42); the publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers).

For children with “high”-risk alleles (codons 634 and 883), thyroidectomy may be delayed to balance risks of surgical complications. These children should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. Metastatic disease is rare if serum calcitonin levels are <40 pg/ml, and neck dissection can often be avoided if cervical adenopathy is not detected by imaging or clinical examination (42,69).

Timing of surgery for individuals with “moderate” risk alleles is most challenging, because this category represents a wide range of penetrance and age of onset associated with different alleles, and there is considerable variability even within families harboring the same variant. For example, a comparison of individual alleles in the moderate risk category (previously ATA classifications A and B) found a 7-fold higher risk for MTC in individuals with a codon 620 variant compared with individuals carrying a codon 611 variant. The median time to MTC was 19 years for codon 620 variant carriers and 56 years for individuals with a variant of codon 611 (71). Therefore, individualization based on variant-specific data and family history may be considered for reasonable surgical planning. Thyroidectomy may be delayed if the family is willing to pursue annual surveillance with serum calcitonin and thyroid ultrasound with prophylactic surgery offered when there is suspicion for progression. Current guidelines for carriers of “moderate” risk alleles recommend thyroidectomy when calcitonin level demonstrates an upward trend or, if a biopsy has been performed and shows cytological evidence of MTC in a thyroid lesion (66). It is critical that families understand the importance of adhering to routine follow-up in these circumstances. Families may elect to pursue thyroidectomy at an earlier time to decrease anxiety or the burden of annual surveillance. Finally, although ultrasound has multiple applications in evaluation of the thyroid and cervical lymph nodes (it can be used to document a normal gland in at-risk individuals with a family history or positive genetic test and for pre-operative staging), ultrasound appears to be less sensitive then calcitonin for diagnosis of MTC, and so it should not be used to exclude malignancy or delay surgery (72).

Pheochromocytoma

Prior clinical guidelines had advocated initiation of PHEO surveillance at 8 years (43), although according to the more recent ATA guidelines, screening for PHEO should commence at 11 years for carriers of the “high” and “highest” risk alleles, and at 16 years for patients with “moderate” risk alleles (42). As genetically at-risk patients undergo routine bloodwork for MTC surveillance, some clinicians elect to also initiate PHEO screening at an earlier age, when performing MTC screening. Plasma free metanephrines and normetanephrines, or 24-hour urinary fractionated metanephrines, are the currently recommended screening tests (42). Additionally, biochemical screening for PHEO should be performed prior to any planned surgery and pregnancy, regardless of age (42,69). Pre-operative alpha-adrenergic blockade is essential for patients with catecholamine-secreting PHEOs to mitigate risk of intra-operative hypertensive crisis. Imaging in the absence of biochemical evidence of disease is not advised in MEN2. In the pediatric population, if biochemical tests are abnormal, MRI of the abdomen and pelvis, with and without intravenous contrast, is preferred over contrast-enhanced CT, due to the lack of ionizing radiation with MRI.

Hyperparathyroidism

Screening for PHPT with serum calcium (if normo-albuminemic) should begin at 11 years and 16 years of age for “high” and “moderate” risk allele carriers respectively (42). Development of hypercalcemia during surveillance is suggestive of hyperparathyroidism and should be followed-up with contemporaneous measurement of calcium and intact parathyroid hormone (iPTH). Many providers include 25-OH Vitamin D levels [either routinely or in response to elevated intact parathyroid hormone (iPTH)] to exclude hypovitaminosis D as a concomitant secondary cause of hyperparathyroidism. Hypercalcemia in the context of normal or elevated iPTH is diagnostic of hyperparathyroidism and should prompt referral to an endocrinologist and surgeon with experience in managing parathyroid disease to determine indications for and timing of surgery (73).

Surgical excision of abnormal parathyroid tissue is the only definitive cure for PHPT. The surgical approach may include resection of a solitary enlarged gland or total four-gland parathyroidectomy with autotransplantation of parathyroid tissue to the neck or forearm. Transcervical thymectomy is often performed at the same time as parathyroidectomy because of the increased risk of supernumerary (or intrathymic) parathyroid glands (and, in the case of MEN1, to reduce the risk of thymic NETs) (74,75). The parathyroid glands may also be removed and autotransplanted during prophylactic thyroidectomy in individuals harboring a RET genotype associated with a high risk for PHPT. However, for patients with “moderate” risk alleles who have both a lower risk for metastatic disease (in cases of non-elevated calcitonin levels) and a low risk for PHPT, central neck dissection should be avoided during thyroidectomy, to preserve the parathyroid glands (76). PHPT is not a feature of “highest” risk codon 918 variants, and so preserving the parathyroid glands when performing surgery in infancy should be a priority. Given the inherent surgical challenges associated with thyroidectomy in infancy, the importance of an experienced surgeon cannot be overstated.

Preoperative imaging of a parathyroid adenoma typically includes ultrasound and/or dual-phase ^99mTc-sestamibi scintigraphy with SPECT/CT (if available), referred to as a “parathyroid scan”. The combination of these two tests is highly sensitive for the localization of parathyroid adenoma. The parathyroid scan offers the additional opportunity to detect developmental variants including intrathyroidal or mediastinal parathyroid tissue (77).

Individualization of Care

Pathogenic RET variants afford a significant opportunity to prevent metastatic disease by adopting prophylactic management and individualization of care based on a patient’s variant status. Ongoing collection of data and outcomes will be necessary to develop the most accurate, variant-specific risk estimates to guide families and clinicians, particularly among carriers of “moderate” risk alleles, in whom disease manifestations can be widely varied. We also recognize the importance of patient preference in determining age at prophylactic thyroidectomy (early thyroidectomy vs. active biochemical and radiographic surveillance) and advocate a mutual decision-making process shared by clinician and patient, balancing disease risk with those of intervention for those with “High” and “Moderate” risk alleles. Among patients at risk for non-adherence to surveillance, appropriate care mandates that strong consideration be given to early prophylactic thyroidectomy to reduce risk of late-presentation with metastatic disease (which is incurable). Patients with pathogenic RET variants should ideally be followed at centers with expertise in interpretation of genetic risk, biochemical analyses, surgical expertise and resources for supporting long-term follow-up. Ongoing molecular research should be complemented with studies aimed at mitigating risk, as well as enhancing communication and adherence to screening, in order to optimize outcomes for these patients.

Multiple Endocrine Neoplasia 4 (MEN 4) or “CDKN1B-related MEN”

MEN 4 (OMIM 610755) was first described as a unique clinical entity in 2006 (78), although a paucity of affected patients to date has thus far limited the ability to generate a complete picture of the syndrome. It was originally identified in the context of a spontaneous CDKN1B variant arising in a rat colony leading to progressive parathyroid adenomas and bilateral PHEO/paraganglioma in 100% of affected animals, with occasionally noted thyroid C-cell hyperplasia and pancreatic islet hyperplasia (78). Humans with inactivating pathogenic variants in CDKN1B appear to have a more restricted phenotype, most similar to MEN1, with a high incidence predominantly of PHPT (in 100% of affected individuals) (79) and PitNETss (somatotroph, corticotroph and non-functioning adenomas). Despite the animal data, to date, no MEN2-spectrum tumors (MTC, PHEO) have been identified among human carriers. Other manifestations described in affected individuals include gastro-entero-pancreatic neuroendocrine tumors, uterine neoplasms, adrenocortical masses and thyroid tumors (79), although none at high enough frequency to mandate surveillance.

Molecular Genetics of MEN4

Nine pedigrees have been reported thus far with CDKN1B-associated MEN1-like tumor syndrome (78,80–83), with 13 pathogenic germline variants described in humans, including frameshift, nonsense and missense variants (84,85). CDKN1B variants have also been associated with familial isolated parathyroid adenoma (83) and isolated PitNET (86). At present, testing for CDKN1B may be considered for those with PHPT in whom MEN1 variant testing is negative.

CDKN1B encodes the p27^kip1 inhibitor of cell cycle progression. In tumor tissues, pathogenic CDKN1B variants appear to be associated with normal transcript levels, but low or undetectable protein levels, suggesting reduced translation or protein half-life in pathogenesis. Other variants seem to be associated with functional defects that interrupt binding to interacting partners or disrupt nuclear localization (78,80–82,87).

Pre-symptomatic Surveillance for MEN4

Given the paucity of pedigrees with MEN 4, surveillance guidelines have yet to be established. To the best of our knowledge, the youngest patient with CDNK1B-attributable disease presented at age 30 with acromegaly (78). Thus, surveillance is primarily clinical and should concentrate on evidence of growth hormone excess (gigantism/acromegaly) (88) and glucocorticoid excess (Cushing’s syndrome) (89), with concern for either prompting endocrine consultation. In children, routine anthropometric assessment with review of growth charts is relevant, as PitNETs may present with growth acceleration (GH hypersecretion) or growth retardation with weight gain (ACTH hypersecretion, causing Cushing’s Disease). In the absence of data, and based solely on expert consensus, we recommend annual bloodwork for PHPT (total calcium adjusted for serum albumin), as well as biochemical surveillance for secretory pituitary somatotroph adenomas (annual IGF-1) beginning at adolescence. A role for baseline or serial pre-symptomatic CNS imaging has not been established.

CDC73-Related (Hyperparathyroid-Jaw Tumor) Syndrome

Rare individuals or families with PHPT develop ossifying fibromas of the jaw (distinct from the “brown tumors” of hyperparathyroidism) and occasionally, parathyroid carcinoma (90). Linkage analysis in such pedigrees excluded loci associated with MEN1 or MEN2 and ultimately, linkage was established at chromosomal location 1q31.2 and the term Hyperparathyroid-Jaw Tumor Syndrome (OMIM 145001) was coined (91).

Molecular Genetics of CDC73-Related Tumor Syndrome

CDC73-related (Hyperparathyroid Jaw Tumor, HPT-JT) Syndrome results from truncating (~80%) or missense variants in the CDC73 gene (also known as HRPT-2), which encodes the parafibromin protein (92–95). Loss of nuclear parafibromin staining by immunohistochemistry (IHC) in any parathyroid adenoma or carcinoma should prompt consideration of germline analysis of CDC73(96,97), and, for this reason we advocate parafibromin IHC for all parathyroid neoplasms in young patients. Additionally, while controversial, parafibromin immunoreactivity may help distinguish adenomatous from carcinomatous nodules and may influence prognosis (98–101).

Pathogenic germline variants in CDC73 typically result in single-gland parathyroid adenomas (>70% of affected individuals) (102), ossifying maxillary or mandibular fibromas (25–50%) or infrequently parathyroid carcinoma (~15%) (103,104). Other manifestations of pathogenic germline CDC73 variants include a high rate of benign and malignant uterine tumors (~75% of patients) (102,105) and renal anomalies (~20%) including cysts, hamartomas and, rarely, Wilms tumor (106).

Disease is inherited in an autosomal dominant pattern with high, but incomplete penetrance, estimated at 70–90% (102,105,107). Pathogenic CDC73 variants are identified in 50–75% of patients with HPT-JT and 14% of patients with familial isolated hyperparathyroidism (108). Among pathogenic variant-carriers, hyperparathyroidism may be diagnosed as young as 7 years (109) while fibromas have been described in patients as young as 10 years (93). Thus far, there are no clear genotype-phenotype associations, although carriers of missense variants seem to have a higher likelihood of isolated hyperparathyroidism (92,103).

Surveillance for carriers of pathogenic germline variants in CDC73 should begin at age 5–10 years and should include: 1) annual biochemical screening for hyperparathyroidism (total calcium, corrected for serum albumin); 2) dental panoramic films every 5 years; and 3) renal ultrasound every 5 years. Women of reproductive age are advised to undergo routine gynecologic assessment with uterine ultrasound as clinically indicated (i.e., with menorrhagia or abnormal uterine bleeding) (103).

Patients with hypercalcemia should evaluated for PHPT as described above (MEN2) and, if confirmed, PHPT should be managed in consultation with an endocrinologist, and consideration given to referral to a high-volume parathyroid surgeon (110). Biopsy of suspicious neck lesions in these patients is discouraged due to risk of seeding carcinomatous cells through the biopsy track. Management of other manifestations of CDC73-tumor syndrome should take place under the direction of a relevant subspecialist.

Conclusion

Multiple Endocrine Neoplasia syndromes offer both a challenge and an opportunity to identify disease at early stages and to intervene to mitigate morbidity and mortality by instituting appropriate management of disease manifestations in the context of multidisciplinary care. Clinical and biochemical markers offer clinicians the ability to detect disease and to follow evolution through the course of observation and treatment. An evolving understanding of genotype-phenotype relationships and progression of disease are altering our approach to management of affected patients, with an emphasis on definitive management as early as necessary, within a framework of limiting surgical and medical complications and disease-related mortality.