Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released

Condition: Hyperparathyroidism 2 - HPRT2
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
CDC730007768 (hyperparathyroidism 1; hrpt1)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: CDC730007768
Morbidity from primary hyperparathyroidism / Surveillance of parathyroid hormone and calcium
Complications of osseous fibromas / Surveillance with panoramic radiograph
Morbidity from advanced renal lesions / Surveillance with renal ultrasound

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of hyperparathyroidism 2 (HPRT2; also known as hyperparathyroidism – jaw tumor syndrome) is not well established. Fewer than 300 cases from approximately 100 families have been reported to date. However, the variable penetrance and expressivity of the genes suggest that the real frequency may be underestimated.
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Clinical Features
(Signs / symptoms)
The primary finding of HPRT2 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 10-22% of cases, the pHPT is caused by parathyroid carcinoma. Individuals with pHPT may be asymptomatic or have mild manifestations, but in the case of parathyroid carcinoma severe hypercalcemic crises may occur. Clinical manifestations include nephrolithiasis, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and constipation. 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. Renal cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage renal disease. Women with HPRT2 are at an increased risk for benign and malignant uterine tumors. Women with HPRT2 also have a higher rate of miscarriage and lower rate of fertility.
Two other CDC73-related disorders have been described: hyperparathyroidism 1 (HPRT1; also known as familial isolated hyperparathyroidism) and parathyroid carcinoma. HPRT1 is characterized by the presence of pHPT in the absence of other clinical features. Parathyroid carcinoma 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. Because of true variable expression, early identification of one but not all findings, or failure to identify all clinical features in HPRT2, it is more practical to consider CDC73-related disorders as a spectrum.
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Natural History
(Important subgroups & survival / recovery)
In HPRT2, pHPT has been found in up to 95% of affected individuals, with onset typically in late adolescence or early adulthood and prevalence increasing with age. The median age of diagnosis of pHPT is 27 years (rage 12-58 years) with a prevalence that increases with age. The earliest reported age for pHPT is 7 years, parathyroid carcinoma is 20 years, and metastatic parathyroid carcinoma is 26 years. However, onset may be delayed until the sixth decade, though some older healthy individuals with a pathogenic variant have been reported. Multiglanular synchronous tumors at initial surgery occur in 20% of cases with a second tumor appearing metachronously in 24% of cases. Lower penetrance of pHPT in females compared to males with HPRT2 has been reported. Uterine involvement is the second most common clinical feature and occurs in 57% of affected women. Ossifying fibromas occur in 30-40% individuals and usually are detectable before the third decade of life. Approximately 13-20% of individuals with HPRT2 have kidney lesions.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with a CDC73-related disorder, the following are recommended at initial diagnosis:
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• Evaluation for pHPT with measurement of concomitant intact parathyroid hormone levels and serum calcium concentration (Tier 4)
• Evaluation of standard end organ damage of pHPT (Tier 3)
• Baseline bone density of the lumbar spine, hips, and distal radius by dual-energy x-ray absorptiometry (DEXA) and 24-hour urine collection for calcium in individuals with evidence of pHPT (Tier 4)
• Evaluation for jaw tumors with panoramic jaw x-ray (Tier 3)
• Evaluation for renal lesions with renal ultrasound examination (Tier 3)
• Evaluation for uterine tumors with pelvic ultrasound examination, CT, or MR starting at reproductive age (Tier 3)
• Consultation with a medical genetics professional (e.g., medical geneticist, genetic counselor). (Tier 4)
A recent consensus guideline recommended that patients at risk for hereditary pHPT be identified before surgery due to earlier onset, increased multiglandular involvement, and higher failure rate (i.e., persistent pHPT) after routine surgical treatment compared to sporadic pHPT, and should thus be treated differently. Total parathyroidectomy offers a simple surgical cure for pHPT, but results in permanent hypothyroidism and its associated morbidity. Thus, the surgical approach for treating hereditary pHPT is to obtain and maintain normocalcemia for the longest time possible, avoid hypocalcemia, minimize surgical morbidity, and facilitate future surgery for recurrent disease. Although the optimal surgical approach in CDC73-related pHPT has not yet been established and remains controversial, some consensus guidelines were proposed for more limited approaches. (Tier 2)
Primary hyperparathyroidism during pregnancy may pose increased risks to the mother (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 primary hyperparathyroidism or evidence of adverse effects on the fetus, surgery (preferred in the second trimester) is required for definitive treatment. These women should be managed in conjunction with a maternal-fetal medicine specialist. (Tier 4)
There are currently no well-established surveillance guidelines for CDC73-related disorders. The following recommendations have been proposed:
• Serum testing for biochemical evidence of pHPT [calcium, iPTH, and 25-(OH) vitamin D] annually
• Consider periodic parathyroid ultrasound examination for the detection of non-functioning parathyroid carcinoma, which can develop on rare occasions
• Dental panoramic x-ray with neck shielding at least every five years; dental providers should be notified of the diagnosis and the need for monitoring for osseous fibromas of the maxilla and mandible
• Individuals who have undergone surgery for a jaw tumor require closer follow-up for possible tumor recurrence
• Monitor for kidney lesions by renal ultrasound examination at least every five years, starting at the age of diagnosis
• For women, starting at reproductive age, lifelong monitoring for uterine tumors with routine gynecologic care (including pelvic examination) and pelvic ultrasound examination in women with a menstrual disorder (particularly abnormal uterine bleeding or menorrhagia); care providers in obstetrics and gynecology should be notified of the risk of uterine tumors. (Tier 4)
Circumstances to Avoid
Individuals with CDC73-related disorders should avoid:
• Dehydration
• Radiation exposure
• Biopsy of extrathyroid tissue in the neck, which increases the risk of seeding of a possible parathyroid carcinoma. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
No genetic mutation prevalence information has been provided for the Adult context.
(Include any high risk racial or ethnic subgroups)
The main finding of HPRT2, pHPT, is found in almost 100% of CDC73 mutation carriers. (Tier 3)
Among affected individuals with HPRT2, the following outcomes have been reported:
• Ossifying fibromas of the mandible or maxilla: 30-40%
• Parathyroid cancer: 22%
• Kidney lesions: 13-20%
• Uterine involvement: 57%. (Tier 3)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available for the Adult context.
HPRT2 has variable expression. (Tier 4)
The same pathogenic variant can cause all three phenotypes of CDC73-related disorders: HPT-JT, HPRT1, and parathyroid carcinoma. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified include imaging and biochemical surveillance and avoidance of dehydration, radiation, and certain biopsy technique which could be burdensome to the patient. In addition, surgical management of pHPT can result in permanent hypoparathroidism, laryngeal nerve injury, and the likelihood of repeat surgery due to recurrence.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Interventions identified include imaging and biochemical surveillance and avoidance of dehydration, radiation, and certain biopsy technique which could be burdensome to the patient. In addition, surgical management of pHPT can result in permanent hypoparathroidism, laryngeal nerve injury, and the likelihood of repeat surgery due to recurrence. (Tier 4)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
1. 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.
2. MA Jackson, TA Rich, MI Hu, ND Perrier, SG Waguespack. CDC73-Related Disorders. 2008 Dec 31 [Updated 2015 Jan 15]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from:
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