Clinical Guidance

Although no genotype-phenotype correlations for CDC73 pathogenic variants have been formally established to date, it has been suggested that pathogenic missense variants are more likely to be associated with the FIHP phenotype; pathogenic variants that cause gross disruption of the protein product are more likely to be associated with the HPT-JT phenotype. However, some variants (e.g., , ) have been reported in association with more than one CDC73-associated phenotype . Families with FIHP appear to have a higher ratio of missense to frameshift/nonsense variants than families with HPT-JT syndrome (4/7 vs 3/38, respectively) [, , , , , , , , , ]. A study of 419 individuals with a CDC73 germline pathogenic variant suggested several genotype-phenotype correlations .

Source: GeneReviews — "CDC73-Related Disorders"

Penetrance

While the penetrance in HPT-JT syndrome is estimated at 80%-90%, lower penetrance in females has been reported in two families and was closer to 70% in two different studies . The overall age-related penetrance in a Dutch population was estimated to be 11% at age 25 years, 65% at age 50 years, and 83% at age 70 years . In a series of 61 individuals, 93% showed some manifestation of HPT-JT syndrome by age 40 years .

Source: GeneReviews — "CDC73-Related Disorders"

Diagnostic Criteria

Suggestive Findings

CDC73-related disorders should be suspected in individuals with any of the following clinical, family history, laboratory, radiographic, and/or histopathology features.

Clinical features

• Primary hyperparathyroidism and ossifying fibroma(s) of the jaw

• Primary hyperparathyroidism with age of onset 45 years and cystic, atypical, and/or malignant parathyroid histology

• Childhood- or adolescent-onset primary hyperparathyroidism

• Childhood-onset ossifying fibroma(s) of the maxilla or mandible. Note: The frequency of CDC73 pathogenic variants in individuals with apparently sporadic ossifying fibromas of the jaw appears low ; however, this has not been extensively studied .

Source: GeneReviews — "CDC73-Related Disorders"

Differential Diagnosis

The following disorders should be considered in the differential diagnosis of CDC73-related disorders. Primary Hyperparathyroidism/ Familial Isolated Hyperparathyroidism Sporadic primary hyperparathyroidism. Primary hyperparathyroidism has a prevalence of one to three in 1,000 in the general population, with a female-to-male ratio of approximately 2.5:1 . Sporadic primary hyperparathyroidism is typically caused by a single parathyroid adenoma, with peak age of onset in the sixth decade of life. Sporadic atypical parathyroid adenomas do not tend to show loss of CDC73 staining . Hereditary primary hyperparathyroidism/ familial isolated hyperparathyroidism. See . Table 2. Genes of Interest in the Differential Diagnosis of Primary Hyperparathyroidism/ Familial Isolated Hyperparathyroidism

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual identified to have a pathogenic variant in CDC73, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

CDC73-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Primary hyperparathyroidism

| • Measurement of concomitant serum calcium iPTH

• Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of iPTH or unexpectedly "normal" calcium concentrations

| Beginning by age 10 yrs

24-hour urine calcium-to-creatinine clearance ratio | In persons w/hypercalcemia

DXA scan to assess bone density of lumbar spine, hips, distal radius | As indicated

Jaw tumors

| Panoramic jaw x-ray w/neck shielding | Beginning at diagnosis

Renal lesions

| Renal US is preferred; CT /or MRI as clinically indicated

Uterine tumors

| • Pelvic exam as part of routine gynecologic care

• Pelvic US is preferred; CT /or MRI as clinically indicated

| Beginning in women at reproductive age

Genetic counseling

| By genetics professionals1 | To inform affected persons their families re nature, MOI, implications of CDC73-related disorders to facilitate medical personal decision making

DXA = dual-energy x-ray absorptiometry; iPTH = intact parathyroid hormone; MOI = mode of inheritance; US = ultrasound

1. Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Source: GeneReviews — "CDC73-Related Disorders"

Clinical Guidance

The following should be avoided:

• Dehydration

• Radiation exposure to the neck

• Biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue

Source: GeneReviews — "CDC73-Related Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "CDC73-Related Disorders"

Surveillance Guidelines

There are currently no well-established, evidence-based surveillance guidelines for individuals with a CDC73-related disorder. Based on an extensive literature review and to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 5.

CDC73-Related Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Primary hyperparathyroidism/

Parathyroid tumors

| • Measurement of concomitant serum calcium iPTH

• Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of iPTH or unexpectedly "normal" calcium concentrations

| Annually beginning by age 10 yrs

Consider neck US exam for detection of nonfunctioning parathyroid carcinoma. | Periodically as indicated based on serum calcium iPTH levels

Evaluate via localization studies1 for new primary parathyroid tumor or recurrence/progression of malignant disease. | In those w/history of parathyroid carcinoma, who develop a rise in calcium levels

Jaw tumors

| • Regular dental visits

• Note: Dental providers should be notified of presence of a CDC73-related disorder need for monitoring for osseous fibromas of maxilla mandible.

| Every 6 mos

Panoramic jaw x-ray w/neck shielding | At least every 5 yrs beginning at diagnosis

Renal lesions

| • Renal US exam to assess for kidney lesions

• CT or MRI as clinically indicated

Serum creatinine concentrations in those w/kidney cysts | Annually

Uterine tumors

| • Gynecol...

Source: GeneReviews — "CDC73-Related Disorders"