CDC73 (Hyperparathyroidism-jaw tumour syndrome) – risk management

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

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

• Unaffected known or obligate CDC73 gene pathogenic variant carrier
• Those 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 

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

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

*the impact of lifestyle on cancer risk should be discussed e.g. recommend regular exercise, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure. 

Pregnancy

If a woman with a CDC73 gene pathogenic variant develops hypercalcaemia during pregnancy, referral to a specialist high risk pregnancy unit should be considered.

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
• 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

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

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 females with a CDC73 pathogenic variant is approximately 57%.^r The incidence of uterine leiomyomas in females with a CDC73 pathogenic variant is similar to that of the general population.^r  

While malignant uterine tumours have been reported in females with a CDC73 pathogenic variant, they appear to be rare. There is no evidence to support routine surveillance for uterine tumours. Females with a CDC73 pathogenic variant should be aware of the risk of uterine tumours and report any new symptoms to their General Practitioner. Further investigation should be undertaken if clinically indicated.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive testing.

Informing family members about hereditary cancers.

Centre for Genetics Education NSW Health

Genetic Alliance Australia

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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.

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