Genotype-Phenotype Correlations in the Hyperparathyroidism-Jaw Tumor Syndrome

Establishing genotype-phenotype correlations in disorders of hereditary endocrine neoplasia is important for clinical screening, genetic counseling, prognostication, surveillance, and surgical strategy, and may also provide clues about disease pathogenesis. Important genotype-phenotype correlations are recognized, for example, in pheochromocytoma/paraganglioma and multiple endocrine neoplasia type 2A. The presence of such correlations has been less clear in other familial endocrine disorders associated with primary hyperparathyroidism including multiple endocrine neoplasia type 1, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). Characteristic features of HPT-JT, apart from fibro-osseous jaw tumors and uterine lesions, include renal neoplasms, such as Wilms tumor and mixed epithelial and stromal tumor (“renal hamartomas”), and a high incidence of parathyroid cancer. Emerging evidence suggests two different genotype-phenotype correlations in HPT-JT based on the type of variant in the CDC73 tumor suppressor gene. Although multiple CDC73 genotypes can give rise to the Wilms tumor phenotype in HPT-JT, the development of mixed epithelial and stromal tumor of the kidney specifically correlates with the presence of a start-loss variant affecting the initiator methionine codon of parafibromin, the protein product encoded by CDC73. Furthermore, the risk of parathyroid cancer in HPT-JT also appears to correlate with genotype: CDC73 frameshift indel, splice-site, and stop-gain genotypes are associated with a greatly increased risk of parathyroid carcinoma compared to carriers of CDC73 missense and nonframeshift indel variants. The recognition of such genotype-phenotype correlations in HPT-JT may impact genetic counseling, patient care and disease surveillance.

parathyroid cancer, tumor suppressor gene, primary hyperparathyroidism Most cases of primary hyperparathyroidism (PHPT) are sporadic, whereas approximately 2% to 5% of PHPT cases are familial. Among such heritable disorders associated with PHPT and/or hypercalcemia, the most common are multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A, familial hypocalciuric hypercalcemia, the hyperparathyroidism-jaw tumor syndrome (HPT-JT), and familial isolated hyperparathyroidism (FIHP) (1-3). Although the different entities are associated with distinct risk genes, the familial disorders of PHPT can frequently be distinguished clinically by their distinctive phenotypic expressions (1, 4). In disorders of hereditary endocrine neoplasia, it can be valuable to establish and recognize genotype-phenotype correlations. With respect to pheochromocytoma and paraganglioma, for example, genotype-phenotype correlations have been observed in clinicogenetic investigations from multiple centers (5-7). It is accepted that the disease genotype affects the underlying disease biology and can influence disease presentation, clinical course, and recurrence risk. Knowledge of the genotype may allow for more accurate prognostication and furthermore influences imaging strategies used for diagnosis and surveillance (8). It is similarly valuable to recognize any genotype-phenotype correlations among familial syndromes of PHPT that may affect clinical evaluation, prognostication, surveillance, and treatment. Genotype-phenotype correlations are already recognized in endocrine neoplasia arising from germline missense variants in the RET oncogene, including multiple endocrine neoplasia type 2A, since the spectrum of disease manifestations and penetrance of medullary thyroid cancer may depend on the specific amino acid residue of RET affected by the missense variation (9, 10). The presence of possible genotype-phenotype correlations has been less clear in MEN1 (resulting from a germline disease-associated variant in the MEN1 gene) and HPT-JT. Despite years of clinicogenetic analysis of patients and kindreds with MEN1, no clear-cut correlation has yet been established between the pattern of major clinical manifestations (which include, besides PHPT, anterior pituitary tumors and gastroenteropancreatic neuroendocrine tumors) and the specific germline variant in the MEN1 tumor suppressor gene (11-13). In contrast, recent evidence, that will be reviewed in detail later, suggests the presence of at least 2 different genotype-phenotype correlations in HPT-JT associated with CDC73 germline variant, genotypes that may affect the risk of developing mixed epithelial and stromal tumor of the kidney (MEST; previously termed “renal hamartomas”) and parathyroid cancer. The Hyperparathyroidism-Jaw Tumor Syndrome and the CDC73 Gene HPT-JT is an autosomal dominant familial neoplasia syndrome of incomplete and variable penetrance in which PHPT is the most common presenting manifestation (Fig. 1). The syndrome was originally recognized as a distinct clinicogenetic entity by Jackson and coworkers in 1990 (14). The nonparathyroid manifestations of HPT-JT include benign mesenchymal odontogenic tumors of the maxilla and/or mandible classified as cemento-ossifying fibromas (15), renal cysts and/or tumors (discussed in more detail later), and uterine tumors and other abnormalities in women (16-18) (Table 1; Fig. 1). In contrast to sporadic PHPT and other familial syndromes of PHPT in which parathyroid malignancy is rare (<1%), parathyroid carcinoma is frequent in HPT-JT, affecting up to 20% to 30% of those with PHPT (17-21). Table 1. | Location/organ | Manifestations | Comments | |---|---|---| | Jaw: maxilla/mandible | Cemento-ossifying fibromas (a.k.a. ossifying fibromas) | Benign fibro-osseous tumors of odontogenic origin; may occur independently of PHPT; distinct from “brown tumors”; represent an independent expression of germline CDC73 variant (and in some patients may be its only manifestation) | | Kidney | Wilms tumor (a.k.a. nephroblastoma) | Malignant tumor; may occur independently of PHPT (see text and Table 2) | | MEST | Usually benign; may occur independently of PHPT; represent an independent expression of germline CDC73 variant (and in some patients may be its only manifestation); so far observed only with germline CDC73 start-loss variant genotype (see text and Table 3) | | | Cysts | Benign; reported in multiple HPT-JT kindreds; formal studies lacking however to show that presence of renal cysts in some HPT-JT patients is syndromic and not simply coincidental, given the high background of simple renal cysts in the general population (see text) | | | Uterus | Adenosarcomas, adenofibromas, leiomyomas, adenomyosis, endometrial hyperplasia, and multiple recurrent atypical adenomyomatous polyps | Frequently manifest as menorrhagia requiring early hysterectomy; associated with a high incidence of miscarriage | Abbreviations: HPT-JT, hyperparathyroidism-jaw tumor syndrome; MEST, mixed epithelial and stromal tumors of the kidney; PHPT, primary hyperparathyroidism. A germline loss-of-function variant of CDC73 (previously called HRPT2) can be demonstrated in the majority of HPT-JT families (18, 22). Most such deleterious genetic alterations in CDC73 are frameshift or nonsense variants predicted to inactivate gene function (Fig. 2) (19, 23). Partial or complete germline deletion of the CDC73 gene has also been reported in patients and kindreds with HPT-JT (Fig. 2) (24-27). The CDC73 gene encodes the protein parafibromin, predicted to contain 531 amino acid residues (22). Because germline-inactivating variants of the CDC73 gene predispose to the neoplastic manifestations of HPT-JT, parafibromin is a likely tumor suppressor protein. Somatic variants of the CDC73 gene are uncommon in sporadic benign parathyroid tumors (28, 29). In contrast to the observations in parathyroid adenomas, somatic variants of CDC73 are frequently found in apparently sporadic cases of parathyroid carcinoma (30-33). The preferential amplification of the allele harboring the disease-associated CDC73 variant has been documented in some parathyroid cancers (33). Approximately 25% of patients with seemingly sporadic parathyroid carcinoma may carry germline CDC73 variant or deletion, suggesting the possibility of incompletely penetrant or undiagnosed HPT-JT in these cases (18, 30, 34). A minority of patients and families with the FIHP phenotype also carry germline inactivating CDC73 variants, suggesting that this familial disorder may, in some cases, represent an incomplete expression of HPT-JT. Approximately 20% of obligate or confirmed CDC73 variant carriers have no evident manifestations of HPT-JT at the time of initial kindred evaluation (19). Because the penetrance of the clinical manifestations of HPT-JT increases with age among carriers of disease-associated CDC73 variants, lifelong monitoring of initially asymptomatic carriers has been recommended (35). This review will focus on possible genotype-phenotype correlations in HPT-JT that may affect its renal and parathyroid manifestations. Prior study of the uterine manifestations of HPT-JT failed to uncover any obvious correlation with CDC73/HRPT2 genotype (16, 19). A preliminary correlation of jaw manifestations in HPT-JT with the presence of germline CDC73 variants categorized as high-impact (explained later) has been reported (19), but this will likely need to be confirmed when additional clinical information that includes the specific histopathology of jaw lesions becomes available (allowing exclusion of subjects with only “brown” tumors of the jaw), and will not be further reviewed here. The Renal Phenotype in HPT-JT and Its Relationship to CDC73 Genotype Several distinct renal findings have been described in HPT-JT kindreds. Wilms tumor (nephroblastoma) was the first renal phenotype reported in association with HPT-JT. The association was only able to be made retrospectively, however, by consideration of a family described by Kakinuma et al in 1994 that included 3 sisters with PHPT: 1 (the proband) with metastatic Wilms tumor and uterine leiomyomata leading to early hysterectomy, 1 sister with cementifying jaw fibroma, and the third sister with parathyroid cancer (36). Although this family was considered FIHP at the time of ascertainment in 1994, in retrospect the family almost certainly represents a phenotype currently described as syndromic HPT-JT. To date, 4 HPT-JT families, including the family described by Kakinuma and coworkers, have been reported with Wilms tumor (Table 1). The germline CDC73 genotype has been reported (or can be inferred) in 3 of these 4 families: 1 family carries a p. Arg9X truncating variant (22, 37), another carries a duplication/insertion variant in exon 1 resulting in a frameshift (14, 37-39), and the third family harbors a p. L95P missense variant (17, 40) (Table 2). Thus at least 3 distinct CDC73 germline genotypes can be associated with the Wilms tumor renal phenotype in HPTJT. Table 2. | Germline CDC73 (HRPT2) genotype in HPT-JT family with Wilms tumor (if known) | Other HPT-JT manifestations in proband or kindred | Year(s) of publication; reference(s) | Comments/kindred ID | |---|---|---|---| | ND | PHPT, JT, PC, UL | 1994 (36) | Family described as FIHP but, in retrospect, almost certainly HPT-JT given expression of JT (cementifying fibroma), PC, and UL in the kindred | | p. Arg9X, (exon 1 c.25C > T) | PHPT, JT | 1995, 2002 (22, 37) | K11690 in (37), Kindred-15 in (22) | | p. Tyr11CysfsX17, (exon 1 c.12_31dup)a | PHPT, JT | 1958, 1990, 1995, 1999 (14, 37-39) | K11687 in (37) and (39) | | p. L95P, (exon 3 c.284T > C) | PHPT, JT, UL | 2010, 2023 (17, 40) | Family DK-1101 in (17). Sequencing of Wilms tumor DNA identified a somatic CDC73 pathogenic variant in the trans allele, p.M1 V (c.1A > G) (17). | Abbreviations: FIHP, familial, isolated hyperparathyroidism; HPT-JT, hyperparathyroidism-jaw tumor syndrome; JT, jaw tumors; ND, not determined; PC, parathyroid cancer; PHPT, primary hyperparathyroidism; UL, uterine leiomyomata. a The CDC73 germline genotype in kindred K11687 was inferred from the following evidence: Hobbs and coworkers demonstrated in 1999 that affected members of HPT-JT kindreds K11687 and K3304 shared a 2.2-cM region of haplotype at the HRPT2 locus of chromosome 1q, and likely shared a common ancestor (39). In 2002, the CDC73 germline genotype in kindred K3304 (Kindred-16 in Carpten et al) was reported as a 41-bp duplication/insertion in exon 1 resulting in a frameshift (22). This genotype was apparently updated in 2010, as seen in Table 1 of Newey et al (41), to CDC73 p. Tyr11CysfsX17, exon 1 c.12_31dup. Subsequently, a different renal phenotype associated with HPT-JT was reported by Teh et al in a publication in 1996 (42). Teh et al described 2 unrelated families with HPT-JT: 1 family exhibited “renal hamartomas” in 4 affected members, and the other family contained 2 affected individuals with cystic kidney disease (42). In the family with “renal hamartomas,” other manifestations in affected family members included jaw tumors and PHPT (Table 3). Table 3. | Renal phenotype, number and gender of affected | Germline CDC73 genotype | Other HPT-JT manifestations in proband or kindred | Year(s) of publication; reference(s) | Comments/kindred ID | |---|---|---|---|---| | “Renal hamartomas”a in 4 affected; 1 M, 3F | p. Met1Ile, (exon 1 c.3G > A) | PHPT, JT | 1996 (42) | Family 1, later listed as Kindred-05 in (22) | | 2002 (22) | Kindred-05 | ||| | MEST in 3 affected; 1 M, 2F | p. Met1Ile, (exon 1 c.3G > T) | Menorrhagia/uterine disease | 2019 (43) | | | MEST in proband; 1F | p. Met1Val, (exon 1 c.1A > G) | JT, menorrhagia/uterine disease | 2022 (44) | Abbreviations: F, female; HPT-JT, hyperparathyroidism-jaw tumor syndrome; JT, jaw tumors; M, male; MEST, mixed epithelial and stromal tumor of the kidney; PHPT, primary hyperparathyroidism. a After the original description of this family in 1996 (42), the nomenclature of renal tumors containing both epithelial and mesenchymal stromal components (including renal hamartoma, mesoblastic nephroma, nephroblastic tumor, and cystic nephroblastoma) was revised in 1998 by pathologists Michal and Syrucek to include the new diagnostic category of MEST (45). Subsequently, MEST was listed in the World Health Organization renal tumor classification as a separate entity in 2004 (46). The “renal hamartomas” present in HPT-JT Family 1, and described in (42), were reviewed retrospectively in 2004 and determined to be MEST (47). After the original description of the family with “renal hamartomas” in 1996 (42), the nomenclature with respect to renal tumors was revised within academia. The diagnosis of MEST was introduced by pathologists Michal and Syrucek in 1998 to include renal tumors containing both epithelial and mesenchymal stromal components (45). Subsequently, MEST was listed in the World Health Organization renal tumor classification as a separate entity in 2004 (46). The “renal hamartomas” present in the HPT-JT Family 1, as described by Teh et al (42), were reviewed retrospectively in 2004 and reclassified as MEST (47). The category of MEST subsumed older diagnostic terminology including leiomyomatous renal hamartoma, cystic hamartoma of the renal pelvis, adult type mesoblastic nephroma, cystic nephroblastoma, and adult cystic nephroma (48, 49). Including the family described by Teh et al (42), a total of 3 unrelated HPT-JT families have been reported with the MEST renal phenotype (Table 3). Within these 3 families, 8 affected individuals have MEST of the kidney, 2 males and 6 females (Table 3). This gender asymmetry is consistent with sporadic MEST, which also exhibits a female predominance (50, 51). In contrast to the renal phenotype of Wilms tumor, the HPT-JT-associated manifestation of MEST appears to correlate with a specific CDC73 genotype, namely a start-loss variant involving the initiator methionine of parafibromin (22, 42, 43). It is noteworthy that the exact germline DNA point variant in CDC73 differs among the 3 HPT-JT families with MEST, consistent with their unrelatedness, but all such point variants cause a start-loss by altering parafibromin's initiating codon (Table 3). Renal cysts are also frequently considered to be a feature of HPT-JT. This association likely originated from the previously mentioned 1996 study by Teh et al that described 2 unrelated HPT-JT families, 1 family with “renal hamartomas” as discussed previously, and a second family that contained 2 affected individuals with cystic kidney disease (42). Several subsequent reports have described HPT-JT kindreds with affected members who have renal cysts (52-56). Against these reports, however, it must be considered that renal cysts are common in the general population and that their prevalence increases with age (57-59). Furthermore, in the general population, a diagnosis of PHPT and a history of nephrolithiasis are independent risk factors for renal cysts (60). Thus, careful systematic study of subjects with HPT-JT and appropriate controls will be necessary in the future to clearly define a threshold of renal cyst number, size, complexity, location, and/or laterality, above which a definitive association of this phenotype as a specific syndromic feature of HPT-JT can be established with confidence. Parathyroid Cancer in HPT-JT and Its Relationship to CDC73 Genotype The unique association of HPT-JT with parathyroid cancer was described previously: in other familial syndromes of PHPT (and among those with sporadic PHPT) parathyroid malignancy comprises < 1% of cases, in HPT-JT, as many as 20% to 30% of those with PHPT may have parathyroid cancer (17-21). Multiple cases of parathyroid cancer within FIHP and HPT-JT kindreds were described in the early literature before CDC73 (HRPT2) gene discovery (39, 55, 61-64). Many of these families with cases of parathyroid cancer were then genetically reinvestigated at the time of CDC73 (HRPT2) gene identification in 2002 by Carpten et al (22). It was therefore possible in retrospect to assign germline CDC73 genotypes to such historical kindreds and, in all cases, high-impact germline variants in CDC73, encoding frameshift indels, splice-site disruptions, and stop-gain substitutions were found (Table 4) (22). None of these historical HPT-JT kindreds with parathyroid cancer was found to harbor CDC73 (HRPT2) missense variant (22). Table 4. | Year, first author, reference | Cases of parathyroid cancer in the kindred | Other HPT-JT manifestations in proband or kindred | Kindred ID | Germline CDC73 genotype | |---|---|---|---|---| | Dinnen et al (61) | 1 | PHPT, JT | UK2396, listed as Kindred-19 in (22) | Exon 1, 39delC frameshift | | Streeten et al (62) | 2 | PHPT, JT | DK2862; listed as Kindred-02 in (22) | Gene deletiona | | Wassif et al (63) | 1 | PHPT | SW7004, listed as Kindred-20 in (22) | Exon 3, 306del (15 bp), frameshift/splice variant | | Williamson et al (64) | 3 | PHPT | UK1394, listed as Kindred-09 in (22) | Exon 4, 356delA frameshift | | Hobbs et al (39) | 2 | PHPT, JT | UK3304, listed as Kindred-16 in (22) | Exon 1, 41-bp duplication/insertion, frameshift | | Cavaco et al (55) | 1 | PHPT, JT | UK0799, listed as Kindred-10 in (22) | Exon 2, 165C-G, Tyr55X | Abbreviations: HPT-JT, hyperparathyroidism-jaw tumor syndrome; JT, jaw tumors; PHPT, primary hyperparathyroidism. The possible relationship of CDC73 genotype to the parathyroid cancer phenotype in HPT-JT was subsequently studied methodically and in depth by Li and coworkers (19). A total of 419 individuals with a CDC73 germline pathogenic variant were investigated, 68 patients enrolled in clinical protocols at National Institutes of Health Clinical Center (NCT04969926) that comprised a discovery cohort, and 351 subjects in a validation cohort with clinicogenetic data extracted from the medical literature (19). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype and compared to other phenotypes, including the relative risk of developing PHPT. Among the 419 individuals, the percentage of high-impact CDC73 germline variants (encoding gross deletions, frameshift indels, splice-site disruptions, and stop-gain variants) was significantly higher among the patients with parathyroid cancer compared to all other subjects (19). After combining patients in the discovery cohort and validation cohorts, Kaplan-Meier analysis revealed that those with high-impact variants had a greater than 10-fold higher risk of parathyroid carcinoma compared to those with low-impact variants (missense and nonframeshift indel variants), despite a similar risk of developing PHPT in the 2 groups (Fig. 3) (19). No association was found between the category of pathogenic variant and development of PHPT, kidney lesions, or uterine manifestations (19). These findings suggest a strong correlation in HPT-JT between the CDC73 genotype and the parathyroid cancer phenotype in which subjects with frameshift, stop-gain, and other high-impact variants in CDC73 bear a significantly higher risk.

With Focus on Implications for Clinical Management The evidence reviewed previously suggests the existence of at least 2 different clinically relevant genotype-phenotype correlations in HPT-JT based on the type of variant in the CDC73 tumor suppressor gene. The development of MEST of the kidney appears to correlate with the presence of a start-loss variant of CDC73 affecting the initiator methionine codon (Table 3). How a start-loss variant of CDC73 may specifically impact the pathogenesis of MEST of the kidney is at once a challenging and fascinating question and will undoubtedly require further basic scientific investigation. The necessary future basic science exploration of this genotype-phenotype correlation should include functional studies to assess the impact of the CDC73 start-loss variant on the expression, quantity, and stability of the resulting mRNA transcript. Variants at the initiator methionine may completely abolish, or greatly reduce the efficiency of, translation; however, it is possible that the presence of a start-loss variant activates a substitute start codon either upstream or downstream of the usual parafibromin translation start site. This substitute start codon may represent a canonical or noncanonical (ie, non-AUG) translation initiation site. In this scenario, it is difficult to know if an alternative protein isoform might result that contains some or all of the native sequence of the parafibromin tumor suppressor protein encoded by CDC73 (22). It is clear in any case, however, that there is something qualitatively different about the consequences of CDC73 start-loss variant, beyond simply “loss-of-function,” that is tied to the histopathogenesis of MEST of the kidney in the context of HPT-JT. MEST of the kidney is usually benign but has malignant potential and a minority of cases can be aggressive (51). Presenting symptoms may include flank pain, hematuria, urinary tract infections, and abdominal mass, and it can also be diagnosed following an incidental finding on abdominal imaging. In the context of HPT-JT and germline CDC73 variant, multiple family members may develop MEST (42, 43) (Table 3). In contrast to MEST, Wilms tumor in HPT-JT has been documented in kindreds with a variety of germline pathogenic CDC73 variants; no obvious genotype-phenotype correlation has yet been described (Table 2). An unexpected potential connection between the CDC73-associated renal neoplasms was the documentation of a somatic CDC73 p.M1 V (c.1A > G) start-loss pathogenic variant in Wilms tumor DNA from a patient with germline CDC73 L95P missense variant (17, 40). Given the established malignant potential of Wilms tumor, and the knowledge that a minority of renal MEST tumors may also behave aggressively, it could be argued that CDC73 gene testing belongs on multigene panels that screen for hereditary renal cancers. At the time of this writing, the hereditary renal cancer gene panels offered by established centers like the Mayo Clinic, InVitae/Labcorp, and GeneDx do not include CDC73. On the other hand, the presence of high-impact germline CDC73 variants appears to correlate with a greatly increased risk of parathyroid cancer in HPT-JT (Fig. 3) (19). The mechanism has been proposed to involve disruption of the conserved C-terminal domain of parafibromin, which is universally predicted to result only from the high-impact category of CDC73 variants (19). Thus far, only 1 large-scale study has demonstrated this correlation between high-impact germline CDC73 variants and the parathyroid cancer phenotype (19). The results are entirely consistent however with the germline CDC73 genotypes identified by Carpten et al (22) from kindreds with parathyroid cancer in the context of FIHP and HPT-JT from the earlier literature, all of which demonstrated high-impact variants in retrospect (Table 4) (39, 55, 61-64). The results are also consistent with studies that performed targeted gene sequencing or whole exome sequencing of parathyroid carcinomas and found that all subjects harboring germline CDC73 (HRPT2) variants had variants in the high-impact category (30, 31, 33). This observation has several clinical implications. The first concerns genetic counseling and disease surveillance. Subjects and families known to harbor germline CDC73 variants in the high-impact category should be educated and receive genetic counseling reflecting their potentially increased risk of parathyroid carcinoma. Based on the evidence presented previously, individuals and kindreds harboring CDC73 variants in the high-impact category should be surveilled closely for the development of functional and potentially nonfunctional parathyroid cancer. In the absence of clinical signs and symptoms of hypercalcemia that would prompt an immediate evaluation for PHPT, this should include biochemical screening with serum calcium and intact PTH determinations annually after 10 years of age (18, 65), and cervical ultrasound every 2 years even in the face of negative biochemistry. On the contrary, patients with CDC73 variants in the low-impact category (such as missense variants) and who therefore appear to have a lower risk of parathyroid carcinoma may be eligible for less frequent surveillance. In the absence of clinical signs and symptoms of hypercalcemia that would appropriately trigger an earlier evaluation for PHPT, this should entail biochemical screening for HPT every 1 to 2 years beginning at age 10 years and cervical ultrasound every 2 to 5 years. Because there is currently insufficient evidence-based, authoritative, clinical data to ascertain the optimal frequency of surveillance for patients harboring CDC73 variants in the high-impact vs low-impact categories, the screening recommendations previously presented, though based on best clinical judgment, must be considered tentative. The apparent correlation between high-impact germline CDC73 variants and parathyroid cancer may also have implications for endocrine surgeons. Initial surgery in patients with PHPT in the context of HPT-JT typically involves bilateral cervical exploration because of the general awareness of the higher incidence of parathyroid malignancy among HPT-JT patients (66). This has been true, even though such patients may have a single culprit gland identified preoperatively. Because any cervical parathyroid exploration involves risks such as bleeding, postsurgical hypoparathyroidism, and damage to the vocal cords, a more conservative unilateral approach might be considered in patients with low-impact CDC73 variants and intraoperative PTH measurements consistent with successful surgery. A related consideration in reoperated patients with persistent or recurrent PHPT pertains to the potential autotransplantation of excised parathyroid tissue. This is typically done to avoid permanent postsurgical hypoparathyroidism in patients who may have little viable parathyroid tissue remaining. Although this has generally been avoided in patients with HPT-JT because of the awareness of potential parathyroid malignancy and a reluctance to risk iatrogenic metastasis, perhaps reasonable exceptions might be considered for patients with low-impact CDC73 variants and a few other options to avoid permanent postsurgical hypoparathyroidism. Recognition and diagnosis of HPT-JT remains difficult, in part because of its variable and incomplete penetrance in contrast, for example, to MEN1 with its highly penetrant features often recognized in multiple generations at the time of initial patient ascertainment. For this reason, it remains a challenge to assemble sufficiently large cohorts of patients with CDC73-related disorders to perform high-quality clinical studies, including the identification of potential genotype-phenotype correlations. Against this background, it is hoped that the present review of the existing medical literature can provide convincing evidence of correlations that may already be recognizable between CDC73 genotype and the renal and parathyroid manifestations of HPT-JT. Search Strategy and Selection Criteria

in this review were identified by searches of PubMed. Our searches were conducted from November 1, 2023, to November 1, 2024, to identify English-language papers published between September 1970 and August 2024. The search terms “jaw tumor syndrome” and “HPT-JT” and “hyperparathyroidism” were combined with other terms (including “Wilms tumor,” “mixed epithelial and stromal tumor,” “parathyroid cancer,” “parathyroid carcinoma”) using the “AND” Boolean operator between search terms. Among the identified references, we prioritized historically important and most recently published papers. Acknowledgments We are grateful to our past and current colleagues in the Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases for many thoughtful discussions, the fellows of the National Institutes of Health Inter-Institute Endocrinology Training Program; Craig Cochran, Lynn Bliss, and the 5NW patient care staff. Abbreviations - FIHP familial isolated hyperparathyroidism - HPT-JT hyperparathyroidism-jaw tumor syndrome - MEN1 multiple endocrine neoplasia type 1 - MEST mixed epithelial and stromal tumor of the kidney - PHPT primary hyperparathyroidism Contributor Information William F Simonds, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA. Yulong Li, Division of Endocrinology, Metabolism & Lipid Research, John T. Milliken Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA. Smita Jha, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA. Funding This work was supported by the Intramural Research Program of the NIH/National Institute of Diabetes Digestive & Kidney Diseases (NIDDK grant numbers 1ZIADK043006-47, and 1ZIADK043012-12). Author Contributions W.F.S., Y.L., and S.J. designed the overall study and devised the manuscript. W.F.S., Y.L., and S.J. collected information and/or prepared figures. W.F.S. prepared the initial manuscript draft. All authors approved the final version of manuscript. Disclosures The authors confirm that there are no conflicts of interest. Data Availability Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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