Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Incomplete)
• Curation Status (Adult): Released - Under Revision 1.2.2
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: CDC73
• Condition: CDC73-Related Conditions
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• CDC73 ⇔ 0007767 (hyperparathyroidism 1): Assertion Pending
• CDC73 ⇔ 0007768 (hyperparathyroidism 2 with jaw tumors): Assertion Pending
• CDC73 ⇔ 0012004 (parathyroid gland carcinoma): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of hyperparathyroidism 2 (HRPT2; also known as hyperparathyroidism – jaw tumor syndrome or HPT-JT) is not well established. The real incidence of HRPT2 is unknown and might be underestimated. Fewer than 300 individuals from approximately 100 families have been reported to date.
Germline CDC73 pathogenic variants have been identified in 20%-29% of individuals with PC without a known family history of CDC73-related conditions. [1, 2]

Clinical Features

CDC73-related conditions are considered as a spectrum that includes three phenotypes: HPRT2; hyperparathyroidism 1 (HPRT1; also known as familial isolated hyperparathyroidism or FIHP) and parathyroid carcinoma (PC).
The primary finding of HRPT2 is primary hyperparathyroidism (pHPT) and is typically caused by a single parathyroid adenoma which is often cystic. A second parathyroid tumor may occur synchronously or metachronously months to decades after the first tumor. In up to one third of individuals, the pHPT is caused by parathyroid carcinoma (PC). Individuals with pHPT may be asymptomatic may present with nephrolithiasis, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and/or constipation. Severe hypercalcemic crises may occur. Ossifying fibromas of the mandible and/or maxilla may also manifest and, although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. These tumors may be bilateral or multifocal, can recur, and can disrupt normal dentition, impair breathing, and be of significant cosmetic concern. Renal manifestations include kidney lesions (most commonly cysts), renal hamartomas, and (more rarely) Wilms tumor, and adenocarcinomas. Renal cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage renal disease. Females with HRPT2 are at an increased risk for benign and malignant uterine tumors. Females with HRPT2 also have a higher rate of miscarriage and lower rate of fertility.
HRPT1 is typically characterized by the presence of pHPT in the absence of other clinical features. However, individuals with HRPT1 are at risk of developing PC, nephrolithiasis, and osteopenia.
PCs are typically functional, resulting in pHPT and high serum calcium levels. However, nonfunctioning PCs are also rarely described in individuals with a CDC73-related disorder. Clinical manifestations PCs can include the following clinical manifestations: palpable neck mass, renal calculi, hoarseness, difficulty speaking or swallowing, muscle weakness, nausea/vomiting, altered mental status, and bone pain and/or pathologic fractures. [1, 2, 3]

Natural History

In HRPT2, pHPT has been found in almost all affected individuals. pHPT is often the first feature of HRPT2, with onset typically in late adolescence or early adulthood. Hypercalcemia is common in the first decade in HRPT2. The median age of diagnosis of pHPT is between 23-38 years (range 12-58 years) with a prevalence that increases with age. The earliest reported age for pHPT is 7 years. However, onset may be delayed until the sixth decade, though some older healthy individuals with a pathogenic variant have been reported. Multiglandular synchronous tumors occur in up to 20% of individuals with a second tumor appearing metachronously in 24% of individuals. Lower penetrance of pHPT in females compared to males with HRPT2 has been reported. Uterine involvement is the second most common clinical feature and occurs in up to 75% of affected females and can be the presenting manifestation. Most females present with menorrhagia that may require hysterectomy at an early age (mean 35 years). Ossifying fibromas occur in 30-40% individuals, have a female preponderance, usually are detectable before the third decade of life, but have been described in individuals as young as 10 years. Up to 20% of individuals with HRPT2 have kidney lesions, with cystic kidney disease being the most common renal manifestation. The earliest reported age for renal lesions is 6 years (metastatic Wilms tumor).
In HRPT1, pHPT clinical diagnosis occurs at a later age (average 55 years) but may share the “classical” pHPT-associated features such as nephrolithiasis and osteopenia.
The earliest reported age for PC is 8 years, in a female with pulmonary metastases. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs in an individual initially diagnosed with HRPT2, the following are recommended:
•Evaluation for jaw tumors with panoramic jaw x-ray
•Evaluation for renal lesions with ultrasound examination
•Evaluation of standard skeletal and renal end organ damage of pHPT
•Evaluation for uterine tumors with pelvic ultrasound examination, CT, or MRI (starting at reproductive age). (Tier 2) [2]

Individuals newly diagnosed with any CDC73-related condition who have evidence of pHPT should be evaluated using a 24-hour urine calcium-to-creatinine clearance ratio. (Tier 4) [1, 3]

Hypercalcemic individuals (including asymptomatic) with pathogenic variants in CDC73 should be evaluated for pHPT (concomitant calcium and intact [i]PTH levels) and should be managed in consultation with an endocrinologist, with consideration given to referral to a high-volume parathyroid surgeon. (Tier 2) [4]

In hereditary pHPT broadly, the aim of pHPT surgery is to obtain and maintain normocalcemia for the longest time possible, avoid iatrogenic hypocalcemia, minimize surgical morbidity, and facilitate future surgery for recurrent disease. Hereditary pHPT is different from sporadic pHPT, with earlier onset, increased multiglandular involvement and higher failure rate after routine surgical treatment, and therefore should be managed differently. Importantly, due to different gene expression, penetrance, and asynchronous multiglandular involvement among conditions of hereditary pHPT, the surgical approach should be tailored to the gene involved, the individual’s wishes, and surgeon’s experience. (Tier 2) [2]

Given the rarity of CDC73-related conditions and the heterogeneity of the parathyroid phenotype, the optimal surgical approach to pHPT in CDC73-related conditions has not yet been established and remains controversial. Early parathyroidectomy (bilateral exploration) is indicated in individuals diagnosed with HRPT2 because of the increased risk of PC. In HPRT2, like sporadic pHPT, subtotal parathyroidectomy or total parathyroidectomy (with or more frequently without autotransplantation) has been proposed for multiglandular disease. For single-gland involvement, a focused approach with selective parathyroidectomy may be performed. For pHPT in HRPT1 a tailored surgical approach based on intraoperative findings is recommended. (Tier 2) [2]

A review of 283 affected individuals with CDC73 pathogenic variants (101 families) reported an overall rate of recurrence of 24%. One study included in the review reported on outcomes of surgical management of 16 symptomatic individuals (median age of 30.7 years) diagnosed with pHPT. All individuals were in biochemical remission postoperatively. Follow-up (median 3.7 years, range 0.05-13.4 years) showed 20% of individuals had recurrent pHPT. In a second study of 17 individuals with pHPT who underwent surgery, cure (defined as postoperative normalization of calcium and iPTH levels for at least 6 months) was achieved by limited parathyroidectomy in 16 individuals (93.3%). HPT persisted in one individual. Sixteen individuals remained disease free for a mean period of 12.3 years (range 4–27). Recurrent HPT occurred in 3 individuals at 5, 9, and 27 years after initial surgery. (Tier 2) [2]

The following PC management recommendations broadly apply to those associated with CDC73 pathogenic variants (both somatic and germline) as well as sporadic PC. Medical management is for symptomatic benefit and directed at managing the effects of a raised PTH levels and subsequent hypercalcemia. Although there is debate as to which surgical technique should be utilized, the gold standard is en bloc (radical) resection. Surgery should be performed at a reference center, specialized in parathyroid surgery, to improve outcomes and provide the best chance of recovery. All individuals should undergo an ultrasound scan of the neck, and if a PC is suspected, an en bloc resection of the PC and adjacent structures should be performed. A national cancer database study of 555 individuals with PC included those with sporadic and hereditary PC, as well as those with somatic or germline pathogenic variants. The 5-year OS ranged from 84-93%, depending on surgical technique. The authors proposed that individuals who are found to have PC after undergoing local resection for a presumed benign indication may be safely and closely monitored, rather than be committed to the morbidity of an initial radical surgery. (Tier 2) [2, 6]

Complete surgical removal of ossifying fibroma in HRPT2 is the recommended treatment based on the size, location, and symptoms of the lesion. However, complete resection may not be possible in all individuals. (Tier 4) [1, 5]

Treatment of kidney manifestations should be managed per nephrologist recommendations. Surgery is the treatment of choice for individuals with HRPT2 given the malignant potential, sarcomatoid differentiation, and potential for metastatic spread. Since individuals may be at risk for multiple, bilateral renal tumors potentially requiring multiple renal surgeries over their lifetime, nephron-sparing surgery rather than radical surgery is advocated, to preserve renal function. (Tier 4) [1, 5]

In general, pHPT during pregnancy may pose increased risks to the pregnant person (symptomatic hypercalcemia) and to the fetus (intrauterine growth retardation, preterm delivery, intrauterine fetal demise, and/or postpartum neonatal hypocalcemia). Conservative observation may be appropriate for mild asymptomatic hypercalcemia, but for symptomatic pHPT or evidence of adverse effects on the fetus, surgery (preferred in the second trimester) is required for definitive treatment. These individuals should be managed in conjunction with a maternal-fetal medicine specialist. (Tier 4) [1]

Surveillance

Surveillance for carriers of pathogenic germline variants in CDC73 should begin between age 5-10 years and should include:
•Biochemical screening for pHPT (total calcium, corrected for serum albumin) every 6-12 months
•Dental panoramic films every 5 years
•Renal ultrasound every 5 years. (Tier 2) [2, 4]

Females of reproductive age are advised to undergo routine gynecologic assessment, with uterine ultrasound as clinically indicated (i.e., with menorrhagia or abnormal uterine bleeding). (Tier 2) [4]

The following additional surveillance recommendations have been proposed:
•Additional serum testing for biochemical evidence of pHPT [iPTH levels and 25-(OH) vitamin D] annually beginning by age 10 years
•Periodic parathyroid ultrasound examination for the detection of rare non-functioning PC can be considered. (Tier 4) [1, 5]

Circumstances to Avoid

Biopsy of suspicious neck lesions is discouraged due to risk of seeding carcinomatous cells through the biopsy track. (Tier 2) [4]

Individuals with CDC73-related disorders should avoid:
•Dehydration
•Radiation exposure to the neck. (Tier 4) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 2, 4]

Prevalence of Genetic Variants

Among all probands with CDC73-related disorders and pathogenic variants in CDC73, >70% have been identified by sequence analysis, while up to 30% have been identified by targeted deletion/duplication analysis. (Tier 3) [1]

Pathogenic CDC73 variants are identified in 50-75% of individuals with HRPT2, with 80% of these being truncating variants. (Tier 3) [4]

The overall prevalence of heterozygous germline CDC73 pathogenic variants in families with HRPT1 has been estimated to be between 7-26% (Tier 3) [1, 4]

Penetrance

The main finding of HRPT2, pHPT, is found in between 70-100% of individuals with a CDC73 pathogenic variant. (Tier 3) [1, 2, 4, 5]

Among affected individuals with HRPT2, the following outcomes have been reported:
•Parathyroid lesions:
- single-gland parathyroid adenomas: 70-86%
- synchronous multiglandular involvement: 13.9-20%
- parathyroid carcinoma (PC): 10-31%
•Ossifying fibromas of the mandible or maxilla: 11–50%
•Kidney lesions: 13-20% (including cysts, hamartomas, and Wilms tumor)
•Uterine tumors (benign and malignant): 38-75% (Tier 3) [1, 2, 3, 4, 5]

Analysis of 20 individuals with pathogenic variants in CDC73 had single-gland disease in 95% at onset, with 23.5% of these individuals experiencing metachronous recurrence in a second gland. (Tier 3) [1]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

The same pathogenic variant can cause all three phenotypes of CDC73-related conditions: HPT-JT, HRPT1, and PC, and the phenotype may vary widely within the same family. Age of onset and disease manifestations also vary widely within the same family. (Tier 3) [1]

Because of true variable expression, early identification of one but not all findings, or failure to identify all clinical features in HRPT2, it is more practical to consider CDC73-related disorders conditions as a spectrum. [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified include imaging and biochemical surveillance and avoidance of dehydration, radiation, and biopsy techniques which could be burdensome. Biochemical surveillance for pHPT should start early and be lifelong. Surgery for CDC73-related disorders represents a special challenge given the substantially increased risk of PC. Surgical management of pHPT leads to an increased morbidity due to the permanent postsurgical hypoparathyroidism that is difficult to treat, especially in young individuals. In one study, 10 of 16 individuals had postoperative transient hypoparathyroidism following initial operation and required calcium supplementation. Two individuals had permanent hypoparathyroidism. Surgery can also cause laryngeal nerve injury, which can be permanent in some cases. The likelihood of repeat surgery due to recurrence has been reported to be about 25%. [1, 2, 5]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Without clinical evidence of jaw tumors, confusion with other hereditary hypercalcemic disorders such as multiple endocrine neoplasia type 1 (MEN1) and familial hypercalcemic hypocalciuria may occur. (Tier 3) [3]

The differential diagnosis between pHPT in HRPT2 and MEN1 is difficult and may depend on surgical and histological findings and the other characteristic lesions specifically associated with each condition. (Tier 3) [3]

Date of Search: 01.05.2017 (updated 11.28.2023)

Reference List

1. Skefos CM, Waguespack SG, Perrier ND, Hu MI. CDC73-Related Disorders. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews((R)). Seattle (WA). (2023) Website: https://www.ncbi.nlm.nih.gov/pubmed/20301744

2. Iacobone M, Carnaille B, Palazzo FF, Vriens M. Hereditary hyperparathyroidism--a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg. (2015) 400(8):867-86.

3. Cristina EV, Alberto F. Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. (2018) 32(1878-1594):861-875.

4. Wasserman JD, Tomlinson GE, Druker H, Kamihara J, Kohlmann WK, Kratz CP, Nathanson KL, Pajtler KW, Parareda A, Rednam SP, States LJ, Villani A, Walsh MF, Zelley K, Schiffman JD. Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res. (2017) 23(13):e123-e132.

5. Torresan F, Iacobone M. Clinical Features, Treatment, and Surveillance of Hyperparathyroidism-Jaw Tumor Syndrome: An Up-to-Date and Review of the Literature. Int J Endocrinol. (2019) 2019(1687-8337):1761030.

6. Roser P, Leca BM, Coelho C, Schulte KM, Gilbert J, Drakou EE, Kosmas C, Ling Chuah L, Wassati H, Miras AD, Crane J, Aylwin SJB, Grossman AB, Dimitriadis GK. Diagnosis and management of parathyroid carcinoma: a state-of-the-art review. Endocr Relat Cancer. (2023) 30(1479-6821).