CDC73 (Hyperparathyroidism-jaw tumour syndrome) – risk management

Hyperparathyroidism-jaw tumour syndrome (HPT-JT) is an autosomal dominant syndrome characterised by primary hyperparathyroidism (PHPT) secondary to parathyroid neoplasm and ossifying fibromas/cemento-ossifying fibromas of the maxilla or mandible.

• Unaffected known or obligate CDC73 gene pathogenic variant carrier
• Individuals at 50% risk of inheriting a CDC73 gene pathogenic variant

Exclusion criteria

• A CDC73 gene pathogenic variant carrier already diagnosed with a relevant cancer/tumour 
• Individual with a variant of uncertain significance

Cancer/tumour type	Risk for this group	General population risk by age 85 years*
Parathyroid carcinoma	23-31% lifetime riskrr	Rare

^*Cancer Institute NSW (CINSW) 2019.  Cancer Statistics NSW: Parathyroid Cancer Incidence Risk by age 85 years (2014 data).

Malignant uterine tumours have been reported but appear to be rare and routine screening is not recommended. See comment on malignant uterine tumours in the evidence section below.

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure. 

Cancer/tumour type	Recommendations
Parathyroid adenoma and/or carcinoma	Surgical	Prophylactic surgery not indicated
	Surveillance	Age	Strategy and frequency
		From age 10 years	Annual fasting calcium, phosphate, vitamin D and parathyroid hormone Annual clinical examination of the neck

Tumour type	Recommendations
		Age	Strategy and frequency
Ossifying fibroma of the maxilla or mandible	Surveillance	From age 10 years	5-yearly orthopantogram (OPG) with neck shielding
Renal complications	Surveillance	From age 10 years	5-yearly renal ultrasound. If renal cysts detected, monitor renal function annually
Benign uterine tumours (e.g. leiomyomas)	Surveillance	There is no evidence to support routine surveillance for uterine tumours. If symptomatic and clinically indicated, further investigation with pelvic ultrasound, and further imaging studies if needed.

Parathyroid neoplasms

Surgical

Compared to individuals with sporadic PHPT, individuals with a CDC73 gene pathogenic variant have an increased risk of the following:

• larger parathyroid tumours which demonstrate distinctive morphological features
• atypical parathyroid adenoma and parathyroid carcinoma
• synchronous or metachronous multiglandular disease
• local or distant recurrence
• postoperative hungry bones syndrome.

These factors should be considered when planning the surgical and post-surgical management of individuals with a CDC73 gene pathogenic variant and PHPT.

Biopsy of suspicious neck lesions in these patients is discouraged due to risk of seeding parathyroid cancer cells, the difficulty it creates in interpreting the pathology of excision specimen and the limited information it provides.^r If there is a suspicion of parathyroid carcinoma (i.e. large tumour on imaging, palpable neck mass, clinical and biochemical evidence of severe hypercalcaemia) then “en bloc” resection is recommended of the affected gland, surrounding tissues, ipsilateral thyroid lobe, ipsilateral normal parathyroid and thymus. This is to reduce the risk of capsular spillage, local seeding and potential need for reoperation on the same side.^r

Rare cases of non-functioning parathyroid carcinoma have been reported in individuals with a CDC73 gene pathogenic variant. Some authors recommend consideration of periodic neck ultrasound in addition to biochemical screening. However, the age of commencement and optimal interval of imaging has not been defined.

Surveillance

The youngest age of PHPT in HPT-JT is reported to be 7 years, while the youngest age of parathyroid carcinoma is reported to be 15 years.^r

There is emerging evidence that CDC73 germline variants that disrupt the C-terminal domain are associated with an increased risk of parathyroid carcinoma and jaw tumours.^r Individuals with pathogenic variants that disrupt the C-terminal domain of the protein and/or that have a family history of parathyroid carcinoma may benefit from closer monitoring for parathyroid carcinoma.

Ossifying fibroma/cemento-ossifying fibroma of the maxilla or mandible

There is currently insufficient available data to indicate whether there is an age at which jaw imaging can be ceased in individuals who have had serial normal imaging. 

Uterine tumours

The lifetime risk of developing uterine tumours in individuals with a CDC73 pathogenic variant is approximately 40-45%.^rr The incidence of uterine leiomyomas in individuals with a CDC73 pathogenic variant is similar to that of the general population.^r  However, there is evidence that there may be a higher number of multiple and / or recurrent adenomyomatous polyps with atypical features in individuals with CDC73 pathogenic variants.^r 

While malignant uterine tumours have been reported in individuals with a CDC73 pathogenic variant, they appear to be rare. There is no evidence to support routine surveillance for uterine tumours. Individuals with a CDC73 pathogenic variant should be aware of the risk of uterine tumours and report any new symptoms to their General Practitioner. Menorrhagia and infertility have been reported in individuals with CDC73 pathogenic variants and may potentially indicate a uterine tumour. Further investigation should be undertaken if clinically indicated with pelvic ultrasound and then further imaging studies if needed.^r

Renal lesions

Wilms tumours have been reported in a small number of patients with CDC73 pathogenic variants from the age of 6 years.^r There is insufficient evidence to estimate the risk of Wilms tumour in the setting of a CDC73 pathogenic variant, but it is likely to be <1%, and the intensive surveillance that would be recommended in other conditions associated with Wilms tumours is not recommended. The current recommendation for 5-yearly ultrasound is predominantly to assess for renal cysts, as multiple bilateral renal cysts resulting in renal impairment and failure have been reported in some individuals with CDC73 pathogenic variants.^rr

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Bibliography

Wasserman, J. D., et al. 2017. "Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood." Clin Cancer Res 23(13): e123-e132.

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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 MEN2B, 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 MEN2B 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. Clin Cancer Res; 23(13); e123-e32. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Guarnieri, V., et al. 2006. "Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance." J Clin Endocrinol Metab 91(8): 2827-2832.

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CONTEXT: Mutations of the HRPT2 gene have recently been implicated in the development of parathyroid carcinoma. OBJECTIVE: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation. PATIENTS, METHODS, AND RESULTS: In a 40-yr-old male previously treated for parathyroid atypical adenoma, we screened the 17 translated HRPT2 exons and their exon-intron boundaries and found a germline frameshift mutation in exon 7 (685delAGAG) predicting a premature stop codon at nucleotides 767-769. Nine family members (age, 33.9 +/- 19.8 yr, mean +/- SD) also carry the mutation, but eight have had normal serum calcium. Biochemical and ultrasonographic evaluation uncovered a 27-yr-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-yr-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma. The index case, 12 yr after surgery, was normocalcemic, but ultrasonography revealed an extrathyroidal nodule in the contralateral hemithyroid tissue that proved to be atypical adenoma. CONCLUSIONS: Our report confirms that germline mutations of HRPT2 gene may be associated with multiple parathyroid neoplasms. Our experience suggests that longitudinal surveillance by serum biochemistry alone may not be 100% sensitive, and addition of routine neck ultrasonography is a readily accepted adjunct that may facilitate earlier disease detection in some families.

Version 7

Date	Summary of changes
10/04/2024	Protocol reviewed at October 2023 cancer genetics reference committee meeting. Discussions continued via MS Teams. Refer to PDF to view previous version of protocol. Version increased to V.7. Review in 2 years.
17/09/2024	Review due date updated as per consensus of the eviQ cancer genetics chairs.

Version 6

Date	Summary of changes
15/09/2023	New eviQ cancer genetics risk management template changes applied - PDF of changes. Version number changed to V.6.

Version 5

Date

Summary of changes

13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template: Summary: Template sentence updated. Target population: Added to exclusion criteria "Individual with a variant of uncertain significance". Cancer/tumour risk management guidelines: Template sentence updated. Lifestyle factors sentence moved above table. Management of associated health problems: Accordion title changed to "Management of associated health issues". Version number increased to V.5.

Version 4

Date

Summary of changes

14/11/2021

Protocol discussed at September 2021 cancer genetics reference committee meeting. Discussions continued via MS Teams. Approved for publication with the following changes made:  Summary: minor wording changes Lifetime risk of cancer/tumour:  Lifetime risk of parathyroid carcinoma: 'Up to 38%' changed to 'Up to 23%' and new reference added New paragraph added below table: 'Malignant uterine tumours have been reported but appear to be rare and routine screening is not recommended. See comment on malignant uterine tumours in the evidence section below.' Lifetime risk of non-cancer manifestations: Hyperparathyroidism risk: '75% by age 70 years' changed to '75-100% by age 70 years' and new reference added Ossifying fibroma/cemento-ossifying fibroma risk: 'Up to 30% by age 40 years' changed to '28.4% by age 40 years' and new reference added Renal lesions risk: 'Up to 13% lifetime risk' changed to '15.6% lifetime risk' and new reference added Cancer/tumour risk management guidelines: 'Annual clinical examination of the neck' added to Strategy and frequency Non-cancer risk management guidelines: new row added to table 'Benign uterine tumours (e.g. leiomyomas)' Evidence for risk management guidelines: Parathyroid neoplasms: reviewed and updated Uterine tumours: reviewed and updated Renal lesions: added. Version increased to V.5. Review in 2 years.

Version 3

Date	Summary of changes
20/12/2019	"Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.3.
18/12/2020	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Lifetime risk of cancer: heading changed to "Lifetime risk of cancer/tumour" Cancer risk management guidelines: Heading changed to "Cancer/tumour risk management guidelines" Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk"  Surveillance: "Age to begin" changed to "Age" Support and information: template wording updated.

Version 2

Date	Summary of changes
28/08/2019	Protocol title changed from 'Risk management for hyperparathyroidism-jaw tumour (HPT-JT) syndrome' to 'CDC73 (Hyperparathyroidism-jaw tumour syndrome) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.2.

Version 1

Date	Summary of changes
19/03/2019	New protocol developed and presented at Nov 2018 RCM. Discussion continued over email and approved for publication. Version V.1. Review second yearly.