CDC73-Associated (Hyperparathyroid-Jaw Tumor) Syndrome – Definition
CDC73-associated (hyperparathyroid-jaw tumor) syndrome (HPT-JT; OMIM #145001) is a rare genetic disorder caused by mutations in the CDC73 gene(also HRPT-2). It predisposes to primary hyperparathyroidism (PHPT) and parathyroid carcinomas, ossifying fibromas of the maxilla and/or mandible, as well as renal and uterine tumors.
Synonyms:
familial primary hyperparathyroidism with multiple ossifying jaw fibromas and familial cystic parathyroid adenomatosis
Gene:
CDC73
Gene product:
Parafibromin
Function:
Subunit of the PAF1 protein complex, acts as a transcription factor
Pattern of inheritance:
autosomal dominant
Prevalence:
unknown
Genotype-phenotype correlation:
missense mutations are more likely to be associated with isolated familial hyperparathyroidism, apart from these, none are known
Penetrance:
80-90%, for women, about 70%
CDC73-Associated (Hyperparathyroid-Jaw Tumor) Syndrome – Diagnosis
Clinical Diagnostic Criteria
- PHPT AND ossifying fibroma(s) of the maxilla and/or mandible
- PHPT AND close relative with HPT-JT syndrome
- Ossifying fibroma(s) of the maxilla and/or mandible AND a close relative with HPT-JT syndrome
Diagnosis Confirmation
Laboratory Parameters
- Serum calcium corrected for serum albumin or ionized calcium:
Elevated in PHPT; extremely elevated in parathyroid carcinoma - Intact parathyroid hormone (iPTH):
Usually elevated in PHPT, may be normal; extremely elevated in parathyroid carcinoma
Imaging
- Orthopantomography and, if necessary, CT to detect ossifying fibromas of the jaw
- Renal sonography (possibly MRI, CT) for the detection of renal tumors
- Sonography of the pelvis (possibly MRI, CT) for the detection of uterine tumors
Genetic Diagnostics
The diagnosis “HPT-JT” is confirmed by detecting a heterozygous mutation of the CDC73 gene using sequence or deletion/duplication analysis.
Differential Diagnoses
- Sporadic, non-genetic PHPT
- Multiple endocrine neoplasia type 1
- CASR-associated diseases
- Multiple endocrine neoplasia type 2A
- Sporadic renal cysts
- Autosomal dominant polycystic kidney disease
- Tuberous sclerosis complex
- Von Hippel-Lindau syndrome
Clinical Presentation
Primary Hyperparathyroidism
- Main finding in HPT-JT and found in up to 95% of patients
- Mostly caused by a single benign parathyroid adenoma, a second may occur syn- or metachronously
- In 10-15% of cases, PHPT is caused by a parathyroid carcinoma
- Occurs mainly in late adolescence to early adulthood
Jaw Tumors
- In 30-40% of HPT-JT patients
- Partly space-occupying lesions with increases in size, partly only radiologically detectable
- Can interrupt dentition and/or impair breathing
Renal Manifestations
- 20% of HPT-JT patients have kidney involvement: mostly cysts, hamartomas or, more rarely, Wilms tumors
- Cystic diseases can be a few small cysts but also bilateral cystic kidneys
Uterine Tumors
- Found in around 75% of female HPT-JT patients, the average age at diagnosis is 35 years
- Can be benign or malignant: endometriosis, adenofibroma, endometrial hyperplasia, leiomyoma and adenosarcoma
Special Features of Treatment
Primary Hyperparathyroidism
As there is usually only a single parathyroid adenoma as the cause of PHPT, a minimally invasive procedure to remove the parathyroid tumor is preferred. This includes
- Preoperative imaging (sonography, scintigraphy with 99mTc, CT/MRI) to localize the abnormal gland
- Intraoperative measurement of iPTH to check that the gland with hyperfunction has been removed
If a parathyroid carcinoma is present, an en-bloc resection, including the ipsilateral thyroid lobe, should be performed.
Jaw Tumors
If possible, the tumor should be completely resected. Drug approaches for tumors that cannot be wholly resected are unknown. Due to the risk of recurrence, patients should attend follow-up examinations.
Renal Manifestations
In the case of cystic diseases, an individual therapy must be determined depending on the extent and appearance. There are no specific guidelines for HPT-JT patients.
Uterine Tumors
In the case of uterine tumors, an individual therapy must be determined depending on the extent and appearance. There are no specific guidelines for HPT-JT patients.
Diagnosis of CDC73-Associated (Hyperparathyroid-Jaw Tumor) Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of CDC73-Associated (Hyperparathyroid-Jaw Tumor) Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
There are no uniform screening recommendations for patients with CDC73 mutations. Based on the currently available literature, the following is suggested:
- Laboratory annually from 5-10 years of age: serum calcium, iPTH, and 25(OH)-vitamin D3
- Regular sonography of the parathyroid glands to detect the rare non-functional parathyroid carcinoma as part of a CDC73 mutation
- Orthopantomography at least every 5 years, regular professional teeth cleaning from the age of 10
- Sonography of the kidneys should be performed at least every 5 years, starting from the time of diagnosis. Serum creatinine should be determined regularly in patients with known cysts.
- Women of childbearing age should undergo regular gynecological examinations. An abdominal or vaginal ultrasound should be performed if there are any abnormalities in the menstrual cycle, if necessary, with further imaging examinations (CT or MRI).
CDC73-Associated (Hyperparathyroid-Jaw Tumor) Syndrome – Further Information
Resources
Unfortunately, we are currently not aware of any support groups for patients with CDC73-associated (hyperparathyroid-jaw tumor) syndrome. New information will be added as soon as it becomes available.
