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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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CDC73-Related Disorders

, MS, CGC, , MD, , MD, , MD, FACS, and , MD.

Author Information
, MS, CGC
Certified Genetic Counselor
Department of Surgical Oncology & Clinical Cancer Genetics
The University of Texas MD Anderson Cancer Center
Houston, Texas
, MD
Assistant Professor, Department of Endocrine Neoplasias and Hormonal Disorders
The University of Texas MD Anderson Cancer Center
Houston, Texas
, MD
Professor, Department of Dental Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
, MD, FACS
Professor, Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
, MD
Associate Professor, Department of Endocrine Neoplasias and Hormonal Disorders
Department of Pediatrics
The University of Texas MD Anderson Cancer Center
Houston, Texas

Initial Posting: ; Last Update: May 24, 2012.

Summary

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

  • Hyperparathyroidism-jaw tumor syndrome (HPT-JT)
  • Parathyroid carcinoma
  • Familial isolated hyperparathyroidism (FIHP)

Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in more than 70% of affected individuals; onset is typically in late adolescence or early adulthood. HPT-JT-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In approximately 10%-15% of cases, 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 are aggressive and continue to enlarge if not treated. Approximately 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 and malignant uterine tumors appear to be common in women with HPT-JT syndrome.

Diagnosis/testing. Diagnosis is based on clinical findings, biochemical findings of primary hyperparathyroidism, ossifying fibroma(s) of the maxilla and/or mandible, family history, and molecular genetic testing. CDC73 (formerly known as HRPT2), which encodes the parafibromin protein, is the only gene in which mutations cause CDC73-related disorders.

Management. Treatment of manifestations: The optimal surgical approach to primary hyperparathyroidism in HPT-JT syndrome has not yet been established; however, because many individuals with HPT-JT syndrome present with a single benign parathyroid tumor, a minimally invasive approach to remove the abnormal parathyroid gland followed by close monitoring for recurrent primary hyperparathyroidism has been suggested. Cinacalcet hydrochloride has been approved for the treatment of severe hypercalcemia secondary to primary hyperparathyroidism in individuals who are unable to undergo parathyroidectomy and for the treatment of parathyroid carcinoma-related hypercalcemia. If parathyroid carcinoma (characterized by extremely elevated serum calcium and iPTH levels, more profound symptoms, and clear radiographic evidence of parathyroid neoplasia) is suspected, an en bloc resection should be considered. Jaw tumors should be treated surgically as indicated by size, location, and symptoms; treatment of choice is complete resection, which may not be possible in all cases. Renal and uterine manifestations are managed on a case-by-case basis.

Prevention of secondary complications: Precautions to reduce the risk for hypoparathyroidism following parathyroid tumor resection.

Surveillance: Starting at age five to ten years: lifelong serum testing for biochemical evidence of hyperparathyroidism every 12 months and panorex dental imaging at least every five years. Those who have undergone surgery for a jaw tumor require close follow-up for possible tumor recurrence. Renal ultrasound examination at least every five years starting at the age of diagnosis; for women, annual pelvic ultrasound examination and regular gynecologic care.

Agents/circumstances to avoid: Dehydration; radiation exposure to the neck; biopsy of extrathyroidal tissue in the neck, which may increase the risk of seeding of a possible parathyroid carcinoma.

Evaluation of relatives at risk: If the family-specific CDC73 germline mutation is known, molecular genetic testing of at-risk relatives around age five to ten years.

Genetic counseling. CDC73-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with HPT-JT syndrome have an affected parent. De novo mutations, including one person with somatic/germline mosaicism, have been reported. Each child of an individual with a CDC73-related disorder has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

GeneReview Scope

CDC73-Related Disorders: Included Disorders 1
  • Familial isolated hyperparathyroidism
  • Hyperparathyroidism-jaw tumor syndrome
  • Parathyroid carcinoma

For synonyms and outdated names see Nomenclature.

1. Forms of these disorders associated with genes other than CDC73 are not addressed in this GeneReview.

Diagnosis

Clinical Diagnosis

Deleterious CDC73 germline mutations cause a spectrum of phenotypes: hyperparathyroidism-jaw tumor (HPT-JT) syndrome, parathyroid carcinoma, and familial isolated hyperparathyroidism (FIHP).

  • Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is clinically established in individuals with any of the following features:
    • Primary hyperparathyroidism AND ossifying fibroma(s) of the maxilla and/or mandible
    • Primary hyperparathyroidism AND the existence of a close relative with HPT-JT syndrome
    • Ossifying fibroma(s) of the maxilla and/or mandible AND a close relative with HPT-JT syndrome
  • CDC73-related parathyroid carcinoma is established in individuals with parathyroid carcinoma and a CDC73 germline mutation. CDC73 mutations have also been found in individuals with clinically non-familial (apparently sporadic) parathyroid carcinoma, parathyroid adenoma, or ossifying fibromas of the jaw.
  • CDC73-related familial isolated hyperparathyroidism (FIHP) is established in individuals with primary hyperparathyroidism and a CDC73 germline mutation who have at least one close relative with primary hyperparathyroidism in the absence of ossifying fibromas.

Of all families reported with a germline CDC73 mutation, 55% have HPT-JT, 21% have FIHP, and the remaining 22% have an apparently sporadic presentation (parathyroid adenoma or carcinoma or ossifying fibroma of the jaw) [Newey et al 2010]. Given that the same mutation may be found in all three phenotypes, individuals with FIHP or an apparently sporadic presentation may actually represent families with HPT-JT syndrome with one of the following:

  • Incomplete expression of other features
  • Early diagnosis before other findings of HPT-JT syndrome develop
  • Other features of HPT-JT that have not been recognized

Testing

Biochemical testing to establish a diagnosis of primary hyperparathyroidism involves measurement of serum concentration of:

  • Intact parathyroid hormone (iPTH). Reference range for normal values varies by laboratory.
  • Total calcium corrected for albumin (preferred) or ionized calcium

Both are usually elevated in individuals with primary hyperparathyroidism; however, in some instances, primary hyperparathyroidism is associated with an elevated serum calcium concentration and an inappropriately normal iPTH.

Parathyroid carcinomas should be considered in individuals with extremely high serum calcium concentration (>12 mg/dL) and extremely high iPTH levels (>3x the upper limit of normal).

Note: Urinary calcium concentrations may also be elevated in primary hyperparathyroidism, but are not necessary or sufficient to make the diagnosis.

Imaging studies. The panoramic x-ray and/or classic mandibular series are easy to obtain and cost-effective in diagnosing jaw tumors in individuals with HPT-JT. These lesions can be radiopaque, but more often are radiolucent when compared with sporadic mandibular ossifying fibromas, which tend to appear as mixed radiolucent/radiopaque lesions [Aldred et al 2006].

Note: The panoramic x-ray interpretation must be correlated with clinical and, in some cases, tissue examination. Interpretation of these types of x-rays should be done by someone familiar with the variables of anatomy and nuances of the panoramic x-ray. Computed tomography is a useful adjunct in the diagnosis and follow-up of ossifying fibromas.

Renal lesions can be detected with renal ultrasound examination, CT, and/or MRI.

Uterine tumors can be detected with pelvic ultrasound examination, CT, and/or MRI.

Molecular Genetic Testing

Gene. CDC73 (formerly known as HRPT2), which encodes the parafibromin protein, is the only gene in which mutations cause CDC73-related disorders.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in CDC73-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CDC73Sequence analysis 4 / mutation scanning 5Sequence variantsVaries by phenotype 6, 7, 8
Deletion/duplication testing 9Partial and whole-gene deletions/duplicationsUnknown 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.

6. Approximately 58% of probands with clinical features of HPT-JT syndrome [Carpten et al 2002]; 20%-29% of individuals with apparently sporadic parathyroid carcinoma [Shattuck et al 2003, Cetani et al 2004, Cetani et al 2007]; 0%-33% of individuals with familial isolated primary hyperparathyroidism [Cetani et al 2004, Simonds et al 2004, Villablanca et al 2004, Warner et al 2004, Bradley et al 2006, Cetani et al 2006, Mizusawa et al 2006]; ~1% of individuals with early-onset (age<45 yrs) apparently sporadic primary hyperparathyroidism [Starker et al 2012]

7. The frequency of CDC73 mutations in individuals with ossifying fibromas of the jaw has not been extensively studied. Pimenta et al [2006] found germline mutations in one of three individuals with an apparently sporadic ossifying fibroma of the mandible, but not in an individual with an apparently sporadic juvenile ossifying fibroma of the mandible. Haag et al [2008] and Kutcher et al [2013] reported individuals with germline CDC73 mutations who had an apparently sporadic ossifying fibroma and later developed primary hyperparathyroidism.

8. Of families with a CDC73 germline mutation identified by sequencing, approximately 88% of mutations could be detected by sequencing exons 1-7 and surrounding intron-exon junctions [Iacobone et al 2009, Newey et al 2010, Panicker et al 2010, Rekik et al 2010, Wang et al 2010, Cavaco et al 2011, Frank-Raue et al 2011, Pichardo-Lowden et al 2011, Siu et al 2011, Starker et al 2012, Kutcher et al 2013]. The remaining 12% of reported germline CDC73 mutations identified by sequencing were found in exons 8 or 13-16. A founder mutation in exon 8 (c.766_767delGT) has been found in Roma families from Portugal [Cavaco et al 2004].

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. The authors report FIHP in two sisters with young-onset cystic and recurrent parathyroid tumors who have a complete deletion of CDC73 [Authors, unpublished]. A kindred with HPT-JT (a 25-year-old male with a cystic parathyroid adenoma and a woman with parathyroid carcinoma with initial onset of hypercalcemia at age 33) has also been reported to have a complete CDC73 deletion [Caron et al 2011, Cascon et al 2011, Domingues et al 2012]

Testing Strategy

To confirm/establish the diagnosis in a proband. CDC73 germline mutation testing should be considered in individuals with the following:

  • Primary hyperparathyroidism and ossifying fibroma(s) of the jaw
  • Primary hyperparathyroidism with young-onset (age <45 yrs) disease and cystic, atypical, and/or malignant parathyroid histology
  • Children diagnosed with ossifying fibroma(s) of the maxilla or mandible
  • Primary hyperparathyroidism with absence of nuclear parafibromin staining in parathyroid tumor as demonstrated by immunohistochemistry
  • Primary hyperparathyroidism or ossifying jaw fibroma and a personal or family history of HPT-JT-associated conditions, such as Wilms tumor or other genitourinary disease
  • Familial primary hyperparathyroidism with negative genetic testing for multiple endocrine neoplasia type 1

Molecular genetic testing could be stratified, as follows:

1.

Perform sequence analysis of exons 1-7 and surrounding intron-exon junctions.

2.

If no pathogenic mutation is identified in exons 1-7, consider sequence analysis of the remaining exons.

3.

If sequence analysis does not demonstrate a pathogenic mutation, consider deletion/duplication analysis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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

  • Hyperparathyroidism-jaw tumor (HPT-JT) syndrome
  • Parathyroid carcinoma
  • Familial isolated hyperparathyroidism (FIHP).

Hyperparathyroidism-Jaw Tumor (HPT-JT) Syndrome

Primary hyperparathyroidism, the main finding of HPT-JT syndrome, has been found in up to 95% of affected individuals; the prevalence increases with age. In most cases, HPT-JT-associated primary hyperparathyroidism is caused by a single benign parathyroid adenoma, which is often cystic or has atypical histologic features. A second parathyroid tumor may occur synchronously or metachronously months to decades after appearance of the first tumor. In approximately 10%-15% of cases, primary hyperparathyroidism is caused by parathyroid carcinoma. Non-functioning parathyroid carcinomas have also been reported [Guarnieri et al 2006].

The age-related penetrance of primary hyperparathyroidism in HPT-JT syndrome is not well established but onset is typically in late adolescence or early adulthood. The earliest reported age of hypercalcemia is seven years [Pichardo-Lowden et al 2011], the earliest reported age at diagnosis of parathyroid carcinoma is 20 years [Howell et al 2003], and the earliest reported age of metastatic parathyroid carcinoma is 26 years [Marx & Simonds 2006]. However, onset may be delayed until the sixth decade [Bradley et al 2006].

Individuals with primary hyperparathyroidism may be asymptomatic or manifest clinical signs including the following:

  • Nephrolithiasis
  • Reduced bone mass
  • Fatigue
  • Muscle weakness
  • Bone or joint pain
  • Constipation

Parathyroid Carcinoma

Clinical manifestations of parathyroid carcinoma can include the following:

  • Palpable neck mass
  • Renal calculi
  • Difficulty speaking or swallowing
  • Muscle weakness
  • Nausea/vomiting
  • Altered mental status
  • Bone pain and/or pathologic fractures

Jaw tumors. 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. Some ossifying fibromas present as an enlarging visible or palpable mass, whereas others are only detected on dental x-ray. Although benign, these tumors can disrupt normal dentition, impair breathing, and be of significant cosmetic concern. Tumors may occasionally be bilateral/multifocal and may recur. The tumors are considered aggressive and continue to enlarge if not treated.

Juvenile fibromas are histologic variants of ossifying fibromas and, when they occur sporadically, tend to occur at a younger mean age than ossifying fibromas. It is not clear whether juvenile fibromas are part of HPT-JT syndrome.

The specific features of jaw tumors that develop in HPT-JT syndrome have not been well defined; in fact, pathologists disagree on the nomenclature used to classify fibro-osseous lesions. Most jaw tumors in HPT-JT syndrome are reported as ossifying fibromas/cementifying fibromas that occur in molar or premolar areas [Chen et al 2003], most often appear to be radiographically radiolucent, and in most cases develop prior to the third decade of life. In contrast, sporadic tumors tend to appear as mixed radiolucent/radiopaque lesions [Aldred et al 2006] and typically develop after the third decade of life [Szabó et al 1995].

Of note, the jaw tumors of HPT-JT syndrome are distinct from the “brown” tumors associated with severe hyperparathyroidism (osteitis fibrosa cystica) and do not resolve following curative parathyroidectomy.

Renal manifestations. Approximately 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported.

Renal cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage renal disease (ESRD) [Tan & Teh 2004]. Cysts have also been observed in association with rare solid tumors, which were histologically similar to mixed epithelial-stromal tumors or adult mesoblastic nephroma (described in one family), or hamartomatous-type tumors [Teh et al 1996, Tan & Teh 2004].

Malignant progression of these tumors has not yet been reported; however, one individual with HPT-JT syndrome had both papillary renal carcinoma and multiple renal cell adenomas [Haven et al 2000].

Wilms tumor has been reported in three unrelated families with HPT-JT syndrome, including an individual who developed bilateral Wilms tumor at age 53 years [Kakinuma et al 1994, Szabó et al 1995].

Uterine tumors. Benign and malignant uterine tumors appear to be common in women with HPT-JT syndrome. In one study, 35 of 44 affected women from 13 HPT-JT kindreds (24/32 mutation positive and 11/12 mutation negative) underwent hysterectomy for menorrhagia at an average age of 35 years (range 23-55 years) [Bradley et al 2005]. In the 15 women who underwent hysterectomy on whom tumor histopathology was available, 23 tumors were identified: extensive adenomyosis (8), adenofibroma (5), endometrial hyperplasia (4), leiomyoma (4), and adenosarcoma (2).

Multiple adenomyomatous uterine polyps were reported in two sisters with likely HPT-JT syndrome [Fujikawa et al 1998]. It was noted that these tumors appeared to have a common embryologic origin from the mesodermal Müllerian duct system.

In addition, the observation that women with HPT-JT syndrome have a higher rate of miscarriage and lower rate of fertility than both unaffected controls and affected males suggests that uterine tumors contribute to decreased reproductive fitness of women with HPT-JT syndrome.

Other tumors. Pancreatic adenocarcinoma, testicular mixed germ cell tumor, and Hürthle cell thyroid adenoma were reported in individuals from a large kindred with HPT-JT syndrome. Papillary thyroid carcinoma and a neurofibroma were reported in individuals with HPT-JT syndrome [Mallette et al 1987, Inoue et al 1995, Haven et al 2000]. However, it is not clear that these tumors are present in a higher frequency in HPT-JT syndrome than in the general population.

Familial Isolated Hyperparathyroidism (FIHP)

FIHP is characterized by primary hyperparathyroidism without other associated features. Individuals with FIHP reported to have a germline CDC73 mutation tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP with no CDC73 mutation. The vast majority of individuals with FIHP and a germline CDC73 mutation have at least one family member with a histopathologic diagnosis of parathyroid carcinoma and/or had a parathyroid adenoma with atypical or cystic features [Cetani et al 2004, Simonds et al 2004, Villablanca et al 2004, Mizusawa et al 2006].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for CDC73 mutations have been formally established to date. However, it has been suggested that missense mutations are more likely to be associated with the FIHP phenotype whereas mutations that cause gross disruption of the protein product are more likely to be associated with the HPT-JT phenotype. In reviewing the reported mutations and associated phenotypes to date, families with FIHP appear to have a higher ratio of missense to frameshift/nonsense mutations than families with HPT-JT (4/7 vs. 3/38, respectively) [Iacobone et al 2009, Newey et al 2010, Panicker et al 2010, Rekik et al 2010, Cavaco et al 2011, Frank-Raue et al 2011, Pichardo-Lowden et al 2011, Siu et al 2011, Starker et al 2012, Kutcher et al 2013].

Penetrance

While the penetrance in HPT-JT syndrome is estimated at 80%-90%, lower penetrance in females has been reported in two families [Teh et al 1996] and was closer to 70% in two different studies [Bradley et al 2005, Iacobone et al 2009].

Anticipation

Anticipation has not been reported in CDC73-related disorders.

Nomenclature

HPT-JT syndrome is also known as familial primary hyperparathyroidism with multiple ossifying jaw fibromas and familial cystic parathyroid adenomatosis.

Prevalence

The prevalence of HPT-JT syndrome is not well established. Approximately 100 affected families have been reported in the medical literature.

CDC73 germline mutations have been reported in the following:

Differential Diagnosis

Primary Hyperparathyroidism/Familial Isolated Hyperparathyroidism

Sporadic primary hyperparathyroidism (not inherited). Overall, primary hyperparathyroidism has a prevalence of one to three per 1,000 in the general population with a female-to-male ratio of approximately 3:1. Sporadic primary hyperparathyroidism is typically caused by a single parathyroid adenoma with a peak age at onset in the sixth decade of life.

Multiple endocrine neoplasia type 1 (MEN1) is the most common known hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of all cases of primary hyperparathyroidism. MEN1-associated primary hyperparathyroidism is characterized by onset in late adolescence to early adulthood (with nearly all individuals affected by age 50 years), multiglandular disease, and histology usually demonstrating parathyroid hyperplasia. Classic MEN1 is also associated with pituitary adenomas and tumors of the endocrine pancreas, primarily gastrinomas and insulinomas. MEN1 germline mutations have also been reported in approximately 20% of individuals with familial isolated primary hyperparathyroidism [Warner et al 2004, Cetani et al 2006, Mizusawa et al 2006].

CASR germline mutations

  • Heterozygous CASR germline mutations are classically associated with familial hypocalciuric hypercalcemia (FHH, also known as benign familial hypercalcemia]. FHH is a benign condition associated with hypercalcemia, low urinary calcium excretion, normal to minimally elevated PTH levels, and frequent hypermagnesemia. Biochemical findings in FHH can overlap with those of primary hyperparathyroidism. However, FHH is not a pathologic process and represents a higher, yet normal, set point for serum calcium concentrations. Therefore, these individuals with FIHP should not be treated with parathyroidectomy, although some individuals with apparent FIHP and a CASR mutation have had primary hyperparathyroidism.
  • Heterozygous CASR mutations have also been reported in 14%-18% of individuals with FIHP [Simonds et al 2002, Warner et al 2004].
  • Homozygous CASR germline mutations are classically associated with neonatal severe primary hyperparathyroidism (NSHPT).

Multiple endocrine neoplasia type 2A (MEN2A). Although primary hyperparathyroidism occurs in approximately 20%-30% of individuals with MEN2A, it is rarely the presenting feature. MEN2A is generally not suspected unless the more common manifestations of MEN2A (including medullary thyroid carcinoma and pheochromocytoma) are present. See Multiple Endocrine Neoplasia Type 2.

An as-yet unknown gene. In most cases of familial primary hyperparathyroidism, an underlying genetic cause cannot be identified. A susceptibility locus has been mapped to 2p13.3-p14 [Warner et al 2006].

Jaw Tumors

Benign lesions that can be confused with HPT-JT on panoramic x-rays are periapical cementoplasia, giant cell reparative granuloma, and idiopathic bone cyst. Benign anatomic variations such as exostosis, mandibular tori, maxillary torus palatinus, and the lingual concavity of the body of the mandible can also be misinterpreted as jaw tumors.

Renal Cysts

Sporadic

The prevalence of at least one renal cyst detected by ultrasound examination in the general population [Ravine et al 1993]:

  • 0% before age 29 years
  • ~1.7% between ages 30 and 49 years
  • 11.5% between ages 50 and 70 years
  • 22% after age 70 years

The prevalence of bilateral renal cysts (at least one cyst in each kidney):

  • 1% between ages 30 and 49 years
  • 4% between ages 50 and 69 years
  • 9% after age 70 years

Syndromic

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple bilateral renal cysts, cysts in other organs (primarily the liver, seminal vesicles, pancreas, and arachnoid membrane), vascular abnormalities, and abdominal wall hernias, with onset typically in adulthood.

Other syndromic conditions associated with renal cystic disease are usually diagnosed by the presence of additional manifestations:

  • Tuberous sclerosis complex (TSC) is also associated with abnormalities of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, subependymal nodules, seizures, intellectual disability/developmental delay), and heart (rhabdomyomas, arrhythmias).
  • von Hippel-Lindau syndrome (VHL) is associated with retinal and/or central nervous system hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, cysts and neuroendocrine tumors of the pancreas, and cystadenomas of the epididymis in males and broad ligament in females.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a CDC73-related disorder, the following are recommended:

  • Evaluation for primary hyperparathyroidism (measurement of concomitant intact parathyroid hormone levels and serum calcium concentration)
  • Baseline bone density of the lumbar spine, hips, and distal radius by dual-energy x-ray absorptiometry (DXA) and 24-hour urine collection for calcium in individuals with evidence of hyperparathyroidism
  • Evaluation for jaw tumors (panoramic jaw x-ray)
  • Evaluation for renal lesions (renal ultrasound examination)
  • Evaluation for uterine tumors (pelvic ultrasound examination) for women starting at reproductive age. Uterine tumors can be detected with pelvic ultrasound examination, CT, or MRI.

Treatment of Manifestations

Primary hyperparathyroidism. The preferred treatment for sporadic primary hyperparathyroidism is parathyroidectomy; most experienced surgeons prefer a minimally invasive approach.

The optimal surgical approach to primary hyperparathyroidism in HPT-JT syndrome has not yet been established. However, because many individuals with HPT-JT syndrome present with a single parathyroid tumor, a minimally invasive approach to remove the abnormal parathyroid tumor followed by close monitoring for recurrent primary hyperparathyroidism has been suggested. Minimally invasive parathyroidectomy requires the use of:

  • Preoperative imaging (e.g., ultrasound examination, 99mTc-sestamibi scanning [often with concomitant SPECT/CT], CT, and/or MRI to localize the abnormal parathyroid gland);

    AND
  • Intraoperative measurement of iPTH (IOPTH) to ensure an adequate resection.

IOPTH involves measurement of serum iPTH at the initiation of the surgery and again at five minutes and ten minutes following excision of the presumed parathyroid tumor. An IOPTH that drops more than 50% in the first five minutes is highly suggestive of cure. The success rate of such a measurement is over 95%. If the IOPTH does not drop more than 50% in five minutes, residual hyperfunctioning tissue likely remains in situ and further exploration is recommended to look for other abnormally hyperfunctioning glands. Standard cervical exploration to visualize all four parathyroid glands is generally not recommended unless it appears that residual hyperfunctioning tissue remains.

In the past, prophylactic total parathyroidectomy has been suggested to reduce the risk of parathyroid carcinoma in HPT-JT syndrome; however, given the difficulty in treating post-surgical hypoparathyroidism, this approach is not widely accepted. Others have recommended standard cervical exploration to visualize all four glands. Regardless of the surgical approach, the risk of recurrent and/or new disease exists; therefore, regular lifelong serum testing for biochemical evidence of hyperparathyroidism is recommended (see Surveillance).

Parathyroid carcinoma is suspected in those with extremely elevated serum calcium and iPTH levels, more profound symptoms, and clear radiographic evidence of parathyroid neoplasia. In this situation, an en bloc resection including the ipsilateral thyroid lobe should occur. Care to prevent fracture of the tumor, which could seed the local area, is critical. Experienced surgeons can usually discern typical benign parathyroid tissue from carcinoma. Benign tissue is peanut butter in color, soft, small, and non-adherent to surrounding structures. Benign tumors are usually oval, round, or kidney-shaped in appearance. In contrast, parathyroid carcinoma is usually hard, firm, white-grey, large, and intimately attached to surrounding structures. In most series, the median maximal diameter of parathyroid carcinoma is between 3.0 cm and 3.5 cm compared with approximately 1.5 cm for benign adenomas.

Cinacalcet hydrochloride (Sensipar®), a calcimimetic that binds to the calcium-sensing receptor, has been approved for the treatment of severe hypercalcemia due to primary hyperparathyroidism in individuals who are unable to undergo parathyroidectomy and for the treatment of parathyroid carcinoma-related hypercalcemia [Messa et al 2011]. Its use in CDC73-related disorders has not been reported, but cinacalcet has proven effective in cases of inoperable parathyroid carcinoma [Silverberg et al 2007].

Jaw tumors. Jaw tumors should be treated surgically as indicated based on the size, location, and symptoms of the lesion. Treatment of choice is complete resection, which may not be possible in all cases. Patients should be followed closely because of the possibility of recurrence.

Renal manifestations. No treatment guidelines for renal manifestations associated with HPT-JT syndrome have been proposed to date. Management guidelines are available for other polycystic kidney diseases, such as autosomal dominant polycystic kidney disease; however, the natural history and likelihood of ESRD is likely to be different in HPT-JT syndrome-associated renal disease. Individuals with evidence of cystic kidney disease should be managed by nephrologists on a case-by-case basis.

Uterine tumors. No treatment guidelines for uterine manifestations associated with HPT-JT syndrome have been proposed to date. Individuals with evidence of a uterine tumor should be managed by a gynecologist on a case-by-case basis.

Prevention of Primary Manifestations

Prophylactic total parathyroidectomy has been suggested to reduce the risk of parathyroid carcinoma. However, given the rarity of parathyroid carcinoma in individuals with HPT-JT syndrome and the difficulty in treating post-surgical hypoparathyroidism, this approach is not recommended.

Prevention of Secondary Complications

The risk of post-operative hypoparathyroidism can be minimized by: ensuring normal preoperative 25-(OH) vitamin D concentrations; recognizing risk factors for hungry bone syndrome preoperatively (e.g., elevated serum alkaline phosphatase concentration); and implementing close postoperative monitoring that includes prompt replacement of calcium and vitamin D as indicated. Minimization of postoperative nausea and vomiting can help prevent an increase in venous pressure, which could lead to oozing and devascularization of the remaining in situ parathyroid glands.

Biopsy of extrathyroidal tissue in the neck should be avoided when possible to reduce the risk of seeding of a possible parathyroid carcinoma.

An en bloc resection should be considered in all patients suspected of having parathyroid carcinoma in order to optimize a surgical cure and prevent positive surgical margins or seeding of parathyroid tissue during removal.

Surveillance

There are currently no well-established surveillance guidelines for HPT-JT syndrome. Based on an extensive literature review, the authors make the following management recommendations:

  • Measure serum concentrations of calcium, iPTH, and 25-(OH) vitamin D (to evaluate for possible coexisting vitamin D deficiency as a cause of elevated iPTH levels or unexpectedly “normal” calcium concentrations) every 12 months starting at age five to ten years.
  • In patients with stable metastatic parathyroid carcinoma who develop a rise in calcium levels, consider the possibility of a new primary parathyroid tumor versus progression of metastatic disease.
  • Consider periodic parathyroid ultrasound examination for the detection of non-functioning parathyroid carcinoma, which has developed on rare occasion in individuals with HPT-JT syndrome [Guarnieri et al 2006].
  • Obtain panorex dental imaging at least every five years, in addition to regular dental hygiene maintenance, starting at age ten years. Dental providers should be notified of the presence of HPT-JT syndrome and the need for monitoring for osseous fibromas of the maxilla and mandible.
  • Monitor for kidney lesions by renal ultrasound examination at least every five years starting at the age of diagnosis. Serum creatinine concentrations should be monitored in those individuals with renal cysts. Individuals with solid lesions should be referred for appropriate subspecialty care.
  • Perform annual pelvic ultrasound examination in addition to regular gynecologic care for women with follow-up CT or MRI for diagnostic purposes as indicated. Pelvic ultrasound examination should be obtained in any woman presenting with a menstrual disorder, particularly abnormal uterine bleeding or menorrhagia. Obstetrics and gynecology providers should be notified of the diagnosis of HPT-JT syndrome and the need for lifelong monitoring for uterine tumors starting at reproductive age.

The age at which genetic testing and surveillance should begin for at-risk relatives is also not well established.

  • The authors recommend considering testing and surveillance for primary hyperparathyroidism and jaw tumors beginning at around age five to ten years, as this is the age of the youngest reported case of hyperparathyroidism and is ten years younger than the earliest reported age of parathyroid carcinoma diagnosis.
  • The age at onset of kidney lesions is not well described; renal ultrasound examination can be considered at time of diagnosis.
  • Uterine tumors have only been reported in adults; lifelong surveillance can begin at reproductive age.

Agents/Circumstances to Avoid

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 a possible parathyroid carcinoma

Evaluation of Relatives at Risk

Molecular genetic testing should be offered to at-risk relatives starting around age five to ten years if the family-specific CDC73 germline mutation has been identified.

When molecular testing for a CDC73 mutation is not possible or not informative, individuals at 50% risk (first-degree relatives of an individual with CDC73-related disorders) should undergo routine evaluation for primary hyperparathyroidism (see Surveillance).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CDC73-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with hyperparathyroidism-jaw tumor (HPT-JT) syndrome have an affected parent. However, de novo cases, including one case of somatic/germline mosaicism in an affected parent have been reported [Villablanca et al 2004].
  • A proband with a CDC73-related disorder may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing if the mutation has been identified in the proband. If a mutation has not been identified in the proband, consider evaluating parents as described in Evaluations Following Initial Diagnosis. Evaluation of parents may determine that one is affected but has escaped previous diagnosis. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with HPT-JT syndrome have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance of the condition, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

Offspring of a proband. Each child of an individual with a CDC73-related disorder has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic family members for CDC73-related disorders is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression in asymptomatic individuals will be. When testing at-risk individuals for CDC73-related disorders, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like CDC73-related disorders) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • Medline Plus
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Endocrine and Metabolic Diseases Information Service
    National Institute of Diabetes and Digestive and Kidney Diseases
    6 Information Way
    Bethesda MD 20892-3569
    Phone: 888-828-0904 (toll-free); 866-569-1162 (TTY)
    Fax: 703-738-4929
    Email: endoandmeta@info.niddk.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. CDC73-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CDC731q31​.2ParafibrominCDC73 homepage - Mendelian genesCDC73

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for CDC73-Related Disorders (View All in OMIM)

145000HYPERPARATHYROIDISM 1; HRPT1
145001HYPERPARATHYROIDISM 2; HRPT2
607393CELL DIVISION CYCLE PROTEIN 73, S. CEREVISIAE, HOMOLOG OF; CDC73
608266PARATHYROID CARCINOMA

Gene structure. CDC73 (formerly known as HRPT2) spans 1.3 Mb of genomic DNA and encodes a 2.7-kb transcript from 17 coding exons [Carpten et al 2002, Bradley et al 2005]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. There are known benign variants in CDC73 [Bradley et al 2006] (Table 2) as well as variants of undetermined clinical significance.

Table 2. Selected CDC73 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Benignc.-11G>A
(5’ of ATG (-11) G>A)
--NM_024529​.3
NP_078805​.3
c.237+28C>T
(Intron 2 (+28) C>T)
--
c.237+28_+31del
(Intron 2 (+28-31) del ccta)
--
c.729+50_51delAG
(intron 7 (+50)delAG)
--
c.1066+8T>C
(intron 12 (+8) T>C)
--
c.1418-17C>G
(intron 15 (-17) C>G)
--
Pathogenic679insAG in exon 7p.Val230GlufsTer28
c.766_767delGT
(255/256delTG)
p.Val256LysfsTer10

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Pathogenic allelic variants. Nonsense, missense, frameshift, and splice-site mutations as well as small deletions and insertions have been reported in individuals/pedigrees affected with hyperparathyroidism-jaw tumor syndrome (HPT-JT) syndrome. More than 44 pathogenic sequence variants have been described for CDC73. CDC73 mutations are predominantly found in exons 1, 2, and 7. Most mutations appear to be unique to individual families; however, some mutations have been found repeatedly in unrelated families, including c.687_688dupAG in exon 7 [Bradley et al 2005]. The mutation c.766_767delGT in exon 8 has been found in several seemingly unrelated families; however, it appears to be a founder mutation in Roma families from Portugal [Cavaco et al 2004].

Normal gene product. The 531-amino acid protein product is called parafibromin. Parafibromin is a subunit of the PAF1 protein complex and likely functions as a transcription factor [Rozenblatt-Rosen et al 2005]. Three putative nuclear localization signals are thought to be located between codons 76 and 92, codons 192 and 194, and codons 393 and 409 [Bradley et al 2005, Hahn & Marsh 2007]. Exon 7 contains a repeat element, (AG)5, and several frameshift mutations altering this motif have been reported.

Abnormal gene product. Most reported germline or somatic mutations in CDC73 are small deletions or insertions leading to frameshifts and predicted truncation of the parafibromin protein. Somatic loss of nuclear parafibromin expression is associated with germline mutations of CDC73 and parathyroid carcinomas, but occurs uncommonly in sporadic benign parathyroid tumors [Tan et al 2004, Gill et al 2006, Cetani et al 2007, Iacobone et al 2007, Juhlin et al 2007]. Similarly, somatic CDC73 mutations are also associated with parathyroid carcinoma, but occur uncommonly in sporadic benign parathyroid tumors [Howell et al 2003, Shattuck et al 2003, Cetani et al 2004, Krebs et al 2005]. Therefore, mutations of CDC73 have been implicated in malignant transformation of parathyroid tumors. It has been suggested that analysis for somatic mutations of CDC73 as well as utilization of immunostaining for nuclear parafibromin expression could be used as markers of malignant potential in parathyroid neoplasms and also as a guide to target genetic screening for HPT-JT syndrome [Tan et al 2004, Gill et al 2006, Cetani et al 2007, Juhlin et al 2007]. The finding of loss of heterozygosity of the wild-type CDC73 allele in parathyroid tumors from individuals with HPT-JT syndrome strongly supports a tumor suppressor role for parafibromin [Bradley et al 2006]. Loss of heterozygosity of the wild-type CDC73 allele has also been observed in sporadic human renal tumors, including clear cell, papillary and chromophobe renal cell carcinomas, as well as oncocytomas and Wilms tumors [Zhao et al 2007].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 5-6-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet SC, Manley S, Culver JO, Acton R, Larsen-Haidle J, Correia LA, Bennett R, Pettersen B, Ferlita TD, Costalas JW, Hunt K, Donlon S, Skrzynia C, Farrell C, Callif-Daley F, Vockley CW. National Society of Genetic Counselors; Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns. 2004;13:83–114. [PubMed: 15604628]
  3. National Cancer Institute Statement: Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute). Available online. Accessed 5-6-14.

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Chapter Notes

Author History

Maria E Cabanillas, MD; University of Texas, Houston (2008-2012)
Mimi I Hu, MD (2012-present)
Jack W Martin, MD (2008-present)
Nancy D Perrier, MD, FACS (2008-present)
Thereasa A Rich, MS, CGC (2008-present)
Steven G Waguespack, MD (2008-present)

Revision History

  • 24 May 2012 (me) Comprehensive update posted live
  • 31 December 2008 (me) Review posted live
  • 12 August 2008 (tar) Original submission
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