CDC73-Related Disorders

Clinical characteristics: The spectrum of CDC73-related disorders includes the following phenotypes:

1. Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism occurs in a vast majority of affected individuals, with onset typically in late adolescence or early adulthood. HPT-JT syndrome-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In at least 10%-15% of individuals, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying fibromas of the mandible or maxilla, also known as cementifying fibromas and cemento-ossifying fibromas, occur in 30%-40% of individuals with HPT-JT syndrome. Although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. Up to 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported. Benign uterine tumors appear to be common in women with HPT-JT syndrome; uterine malignancies have also been reported.

2. Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in primary hyperparathyroidism and a high serum calcium level; however, nonfunctioning parathyroid carcinomas are also rarely described in individuals with a CDC73-related disorder. A germline CDC73 pathogenic variant has been identified in 20%-29% of individuals with parathyroid carcinoma without a known family history of CDC73-related conditions.

3. Familial isolated hyperparathyroidism (FIHP). Characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with CDC73-related FIHP tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP in whom a CDC73 pathogenic variant has not been identified.

Diagnosis/testing: The diagnosis is established in a proband with a germline heterozygous CDC73 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: Parathyroidectomy is the preferred treatment for primary hyperparathyroidism, especially in individuals with HPT-JT syndrome. If parathyroid carcinoma is clinically suspected, an en bloc resection of the parathyroid gland with surrounding adherent tissue and the ipsilateral thyroid lobe should be considered. Intravenous fluids and a bisphosphonate infusion for severe or symptomatic hypercalcemia. Cinacalcet hydrochloride may be used for hypercalcemia in those with inoperable parathyroid adenoma or carcinoma. Calcium and vitamin D as needed for postoperative hypoparathyroidism. Jaw tumors should be treated surgically as indicated by size, location, and symptoms; the treatment of choice is complete resection, which may not be possible in all individuals. Treatment of kidney and uterine manifestations should be managed per nephrologist and gynecologist recommendations, respectively.

Surveillance: Serum calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels annually starting by age ten years. Periodic neck ultrasound as indicated based on serum calcium and iPTH levels. Dental examinations every six months; panoramic jaw x-ray with neck shielding at least every five years. Renal ultrasound at least every five years. Annual serum creatinine in those with kidney cysts. For women of reproductive age, annual gynecologic examination for uterine tumors with pelvic ultrasound every five years.

Agents/circumstances to avoid: Dehydration; radiation exposure to the neck; biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue.

Evaluation of relatives at risk: Molecular genetic testing for the CDC73 germline pathogenic variant identified in the proband should be offered to at-risk relatives by age ten years in order to identify those who would benefit from initiation of surveillance and treatment.

Pregnancy management: Observation for mild asymptomatic hypercalcemia; minimally invasive resection of the parathyroid tumor (preferably in the second trimester) is required for symptomatic primary hyperparathyroidism or evidence of adverse effects on the fetus; management in conjunction with a maternal-fetal medicine specialist.

Genetic counseling: CDC73-related disorders are inherited in an autosomal dominant manner. An individual with a CDC73-related disorder may have inherited a CDC73 pathogenic variant from an affected parent or have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with a CDC73-related disorder has a 50% chance of inheriting the pathogenic variant. Once the CDC73 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.