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CDC73-Related Disorders

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

Author Information

Initial Posting: ; Last Update: April 26, 2018.

Summary

Clinical characteristics.

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

  • Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in up to 95% 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 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. 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.
  • Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning 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 apparently sporadic parathyroid carcinoma.
  • Familial isolated hyperparathyroidism (FIHP). FIHP is 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 by identification of a germline heterozygous CDC73 pathogenic variant on molecular genetic testing.

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. If parathyroid carcinoma is clinically suspected (large tumor on imaging, palpable neck mass, severe presentation of primary hyperparathyroidism), an en bloc resection of the parathyroid gland with surrounding, adherent tissue and the ipsilateral thyroid lobe should be considered. 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. 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. Renal and uterine manifestations are managed on a case-by-case basis.

Prevention of secondary complications: Decrease the risk of postoperative hypoparathyroidism: ensure normal preoperative 25-(OH) vitamin D concentration; recognize risk factors for hungry bone syndrome, such as an elevated alkaline phosphatase level; postoperative monitoring with replacement of calcium and vitamin D. Minimize postoperative nausea and vomiting to prevent devascularization of the remaining in situ parathyroid glands. Avoid biopsy of extrathyroidal tissue to reduce the risk of seeding of a parathyroid carcinoma. Consider en bloc resection in those with suspected parathyroid carcinoma to optimize a surgical cure and prevent positive surgical margins or seeding of parathyroid tissue (parathyromatosis) during removal.

Surveillance: Starting at age five years, serum calcium, intact parathyroid hormone (iPTH), and 25-(OH) vitamin D levels annually, and dental panoramic x-ray with neck shielding at least every five years starting at age ten. 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 and pelvic ultrasound examination as clinically indicated.

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

Evaluation of relatives at risk: If the family-specific CDC73 pathogenic variant is known, molecular genetic testing of at-risk relatives should be offered starting around age five years in order to identify as early as possible those who would benefit from initiation of surveillance, treatment, and/or preventive measures.

Genetic counseling.

CDC73-related disorders are inherited in an autosomal dominant manner. An individual with a CDC73-related disorder may have inherited the disorder from an affected parent or developed it as the result of a de novo pathogenic variant of CDC73. 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. Prenatal diagnosis for pregnancies at increased risk is possible if the CDC73 pathogenic variant in the family is known.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

The diagnosis of a CDC73-related disorder requires a thorough personal and family history as well as molecular genetic testing. Given the variable expressivity and penetrance associated with certain CDC73 pathogenic variants, the resulting phenotype can differ, and the identification of a germline pathogenic variant in CDC73 should be interpreted in the right clinical context in order to establish the most accurate phenotype. No formal diagnostic criteria for CDC73-related disorders have been published. There is currently no published genetic testing algorithm.

Suggestive Findings

CDC73-related disorders should be suspected in individuals with any of the following:

  • Primary hyperparathyroidism and ossifying fibroma(s) of the jaw
  • Primary hyperparathyroidism with young-onset (age <45 years) disease 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 [Chen et al 2016]; however, this has not been extensively studied (see Clinical Characteristics).
  • 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 and absence of:

Laboratory features of primary hyperparathyroidism

  • Elevated total calcium corrected for albumin (preferred) or ionized calcium
  • Elevated or inappropriately normal intact parathyroid hormone (iPTH)

Radiographic features of ossifying fibromas. Panoramic x-ray and/or a classic mandibular series reveals mandibular or maxillary well-circumscribed lesions that are often, but not always, radiolucent and expand the underlying bone. Note: (1) Sporadic mandibular ossifying fibromas tend to appear as mixed radiolucent/radiopaque lesions [Aldred et al 2006]. (2) The panoramic x-ray interpretation must be correlated with clinical and, in some individuals, tissue examination. X-rays of this type should be interpreted by someone familiar with the variables of anatomy and nuances of the panoramic x-ray.

Histopathologic features of resected parathyroid lesions

  • Parathyroid carcinoma
  • Atypical parathyroid adenoma
  • Parathyroid adenoma with or without cystic features
  • Loss of parafibromin expression

Establishing the Diagnosis

The diagnosis of a CDC73-related disorder is established in a proband by the identification of a heterozygous germline CDC73 pathogenic variant on molecular genetic testing. CDC73-related disorders include three clinically and genetically overlapping entities:

  • A diagnosis of hyperparathyroidism-jaw tumor (HPT-JT) syndrome is established in individuals with a CDC73 pathogenic variant and any of the following clinical features:
    • Primary hyperparathyroidism AND ossifying fibroma(s) of the maxilla and/or mandible
    • Primary hyperparathyroidism AND a close relative with HPT-JT syndrome
    • Ossifying fibroma(s) of the maxilla and/or mandible AND a close relative with HPT-JT syndrome
  • A diagnosis of CDC73-related parathyroid carcinoma is established in individuals with parathyroid carcinoma and a germline CDC73 pathogenic variant and no family history suggestive of a CDC73-related disorder (simplex case). CDC73 pathogenic variants have been found in individuals with clinically nonfamilial (apparently sporadic) parathyroid carcinoma and parathyroid adenoma.
  • A diagnosis of CDC73-related familial isolated hyperparathyroidism (FIHP) is established in individuals with primary hyperparathyroidism and a germline CDC73 pathogenic variant who have at least one close relative with primary hyperparathyroidism in the absence of ossifying fibromas. Primary hyperparathyroidism in these families could be caused by parathyroid carcinoma.

It is important to obtain regular personal and family history updates in individuals with CDC73 pathogenic variants, as changes in these histories could also change which CDC73-related disorder is the most accurate diagnosis.

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Many laboratories may only offer concurrent CDC73 sequence analysis and gene-targeted deletion/duplication analysis. However, if a tiered testing approach is available, it is reasonable to consider performing sequence analysis of CDC73 first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found by sequence analysis.
  • A multigene panel that includes CDC73 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and over time. (2) Some multigene panels may include genes not associated with the conditions discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in CDC73-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
CDC73Sequence analysis 3>70% 4
Gene-targeted deletion/duplication analysis 5≤30% 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Bricaire et al [2013]; complete deletion of CDC73 has been reported (see Molecular Genetics).

Sporadic tumors (including parathyroid carcinoma, benign parathyroid tumors, and renal tumors) occurring as single tumors in the absence of any other findings of a CDC73-related disorder may harbor somatic variants in CDC73 that are not present in the germline. In these circumstances predisposition to these tumors is not heritable; however, germline testing should still be performed if a CDC73-associated disorder is suspected clinically, as somatic testing is not suitable for identifying or excluding hereditary disease. For more details, see Cancer and Benign Tumors.

Clinical Characteristics

Clinical Description

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

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

The following sections describe the clinical characteristics that can be seen across the spectrum.

Primary Hyperparathyroidism

Individuals with primary hyperparathyroidism may be asymptomatic or may present with nephrolithiasis, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and/or constipation.

Primary hyperparathyroidism occurs in up to 95% of individuals with HPT-JT syndrome; the onset is typically in late adolescence or early adulthood. The earliest reported age of hypercalcemia is seven years [Pichardo-Lowden et al 2011]. The median age of diagnosis of primary hyperparathyroidism reported by Bricaire et al [2013] was 27 years (range 12-58) in individuals heterozygous for a CDC73 pathogenic variant; the mean age of diagnosis reported by van der Tuin et al [2017] was 32 years ±15 years. Penetrance increases with age: in a Dutch population the penetrance of primary hyperparathyroidism in HPT-JT syndrome at ages 25, 50, and 70 was reported to be 8%, 53%, and 75%, respectively [van der Tuin et al 2017].

In most individuals with HPT-JT syndrome, hyperparathyroidism is caused by a single benign parathyroid adenoma, which is often cystic or has atypical histologic features. Many families segregating a CDC73 pathogenic variant have at least one affected member with a cystic, malignant, and/or atypical parathyroid tumor. A second parathyroid tumor may occur synchronously or metachronously months to decades after appearance of the first tumor. In approximately 10%-15% of individuals with HPT-JT syndrome, primary hyperparathyroidism is caused by parathyroid carcinoma. The earliest reported age at diagnosis of parathyroid carcinoma is eight years in a girl with pulmonary metastases [Davidson et al 2016]. However, onset may be delayed until the sixth decade [Bradley et al 2006]. Non-functioning parathyroid carcinomas have also been reported [Guarnieri et al 2006].

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 [Chen et al 2003]. 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.

The frequency of CDC73 pathogenic variants in individuals with ossifying fibromas of the jaw has not been extensively studied. Pimenta et al [2006] found a heterozygous germline pathogenic variant 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 heterozygous germline CDC73 pathogenic variants who had an apparently sporadic ossifying fibroma and later developed primary hyperparathyroidism. Chen et al [2016] reported 19 children and 21 adults with sporadic ossifying fibromas, and no individual had a germline CDC73 pathogenic variant identified by sequence analysis (deletion/duplication analysis was not performed); two individuals had somatic CDC73 pathogenic variants confined to the ossifying fibroma.

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 usually 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].

Juvenile fibromas are histologic variants of ossifying fibromas that, 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.

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 of HPT-JT kindreds, uterine pathology was described in women who underwent hysterectomy for menorrhagia [Bradley et al 2005]. The following tumors were identified at time of surgery (average age 35 years; range 23-55 years): adenomyosis (8), adenofibroma (5), endometrial hyperplasia (4), leiomyoma (4), and adenosarcoma (2).

Multiple adenomyomatous uterine polyps that appeared to have a common embryologic origin (the mesodermal müllerian duct system) were reported in two sisters with likely HPT-JT syndrome [Fujikawa et al 1998].

In addition, the observation that women with HPT-JT syndrome have a higher rate of miscarriage than unaffected controls and a lower rate of fertility than both unaffected controls and affected males suggests that uterine tumors may 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 in a large kindred with HPT-JT syndrome, as were colon adenocarcinoma, leukemia, papillary thyroid carcinoma, and chronic lymphatic leukemia in other kindreds. 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, Iacobone et al 2009]. However, it is not clear that these tumors are present in a higher frequency in individuals with HPT-JT syndrome than in the general population nor that these tumors were caused by a CDC73 pathogenic variant.

Parathyroid Carcinoma

Clinical manifestations of parathyroid carcinoma can include palpable neck mass, renal calculi, hoarseness, difficulty speaking or swallowing, muscle weakness, nausea/vomiting, altered mental status, bone pain, and/or pathologic fractures. Parathyroid carcinomas are most often associated with extremely high serum calcium concentration (>12 mg/dL) and extremely high iPTH levels (>3x the upper limit of normal). However, non-functioning parathyroid carcinoma has rarely occurred in individuals with a CDC73-related disorder [Guarnieri et al 2006]. A germline CDC73 pathogenic variant has been identified in 18%-29% of individuals with apparently sporadic parathyroid carcinoma (i.e., no family history of syndromic features or primary hyperparathyroidism) [Carpten et al 2002, Shattuck et al 2003, Cetani et al 2004, Cetani et al 2007, Haven et al 2007, Cetani et al 2013, van der Tuin et al 2017].

Familial Isolated Hyperparathyroidism

Familial isolated hyperparathyroidism (FIHP) is 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, and individuals in these families may still develop parathyroid carcinoma. The overall prevalence of heterozygous germline CDC73 pathogenic variants in families with FIHP has been estimated to be between 7% and 26% [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, van der Tuin et al 2017]. A CDC73 pathogenic variant has been identified in approximately 1%-2% of individuals with early-onset (age <45 years), apparently sporadic primary hyperparathyroidism [Starker et al 2012, van der Tuin et al 2017].

The vast majority of individuals with CDC73-related FIHP have had: (a) at least one family member with a histopathologic diagnosis of parathyroid carcinoma; and/or (2) 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

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., c.679_680insAG, c.131+1G>A) have been reported in association with more than one CDC73-associated phenotype [Cardoso et al 2017]. In reviewing the reported pathogenic variants and associated phenotypes to date, 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) [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]. The overall age-related penetrance in a Dutch population was estimated to be 11% at age 25, 65% at age 50, and 83% at age 70 [van der Tuin et al 2017].

Nomenclature

Hyperparathyroidism-jaw tumor (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.

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 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 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 gastroenteropancreatic neuroendocrine tumors, primarily gastrinomas and insulinomas. MEN1 germline pathogenic variants 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]. MEN1 is caused by pathogenic variants in MEN1; inheritance is autosomal dominant.

Multiple endocrine neoplasia type 4 (MEN4; OMIM 610755) is a recently described hereditary endocrine neoplasia syndrome caused by CDKN1B pathogenic variants. The phenotype of MEN4 overlaps with that of MEN1; however, less is known about its penetrance and associated lifetime risk for endocrine tumors. Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1. The proportion of sporadic or familial primary hyperparathyroidism explained by MEN4 remains unknown. Additional endocrine tumors seen in individuals with MEN4 include pituitary adenomas and pancreatic neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1. Inheritance is autosomal dominant.

Familial hypocalciuric hypercalcemia (FHH)

  • Familial hypocalciuric hypercalcemia type 1 (benign familial hypercalcemia) (OMIM 145980) is a benign condition characterized by hypercalcemia, low urinary calcium excretion (assessed via a calcium/creatinine clearance ratio), 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. FHH is caused by heterozygous germline pathogenic variants in CASR.
  • Heterozygous CASR pathogenic variants have also been reported in 14%-18% of individuals with FIHP [Simonds et al 2002, Warner et al 2004].
  • Homozygous CASR germline pathogenic variants are associated with neonatal severe primary hyperparathyroidism (NSHPT) (OMIM 239200).
  • In a smaller proportion of individuals with FHH, germline pathogenic variants in GNA11 and AP2S1 – which cause FHH types 2 and 3, respectively (OMIM 145981, 600740) – have been identified. It is not known whether pathogenic variants in these genes account for any proportion of FIHP.

Familial isolated hyperparathyroidism type 4 (OMIM 617343). Recently, germline activating pathogenic variants in GCM2 have been found in multiple kindreds with familial isolated primary hyperparathyroidism, and early data suggest that individuals with GCM2-associated primary hyperparathyroidism are more likely to have aggressive disease, including a lesser rate of biochemical cure and an increased incidence of parathyroid carcinoma. Individuals in these kindreds do not appear to be at increased risk for other endocrine tumors. Inheritance is autosomal dominant.

Multiple endocrine neoplasia type 2A (MEN2A). Although primary hyperparathyroidism occurs in up to 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. MEN2A is caused by pathogenic variants in RET; inheritance is autosomal dominant. See Multiple Endocrine Neoplasia Type 2.

An as-yet unknown gene. In many individuals with familial primary hyperparathyroidism, an underlying genetic cause cannot be identified. A susceptibility locus has been mapped to 2p13.3-p14 [Warner et al 2006], and inheritance of familial isolated primary hyperparathyroidism is autosomal dominant.

Jaw Tumors

The differential diagnosis for ossifying fibromas of the jaw seen as part of HPT-JT syndrome is dependent on the radiologic characteristics of the lesions, specifically whether they are radiolucent, have mixed radiographic features, or are completely radiopaque [Chang et al 2008]. One of the most important diagnoses to consider is fibrous dysplasia, which is a reactive lesion rather than a true neoplasm. In addition, osseous dysplasia, including focal osseous dysplasia, should be considered [de Andrade et al 2013]. Benign lesions that can be confused with HPT-JT on panoramic x-rays include but are not limited to 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. See Chang et al [2008] and de Andrade et al [2013] for clinicopathologic case series of patients with ossifying fibromas of the jaw, including discussion and review of pertinent differential diagnoses to consider.

Renal Cysts

Sporadic Renal Cysts

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 Renal Cysts

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. In approximately 85% of individuals with ADPKD, pathogenic variants in PKD1 are causative; in approximately 15%, pathogenic variants in PKD2 are causative; inheritance is autosomal dominant.

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

  • Tuberous sclerosis complex 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). Among those in whom a pathogenic variant can be identified, pathogenic variants in TSC1 are found in 31% and pathogenic variants in TSC2 in 69%; inheritance is autosomal dominant.
  • 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. VHL is caused by pathogenic variants in VHL; inheritance is autosomal dominant.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual identified to have a pathogenic variant in CDC73, the following are recommended if they have not already been completed:

  • Evaluation for primary hyperparathyroidism. Measurement of concomitant iPTH levels and serum calcium concentration; measurement of 25-(OH) vitamin D to rule out vitamin D deficiency as a confounder.
  • 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 primary hyperparathyroidism
  • Evaluation for jaw tumors. Panoramic jaw x-ray with neck shielding
  • Evaluation for renal lesions. Renal ultrasound examination preferred; CT and/or MRI as clinically indicated
  • Evaluation for uterine tumors in women starting at reproductive age. Pelvic examination as part of routine gynecologic care; pelvic ultrasound examination (preferred) and other imaging studies (CT and/or MRI) as clinically indicated
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Primary hyperparathyroidism. While the preferred treatment for sporadic primary hyperparathyroidism is parathyroidectomy by a high-volume parathyroid surgeon (most of whom prefer a minimally invasive or targeted 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, benign parathyroid tumor, a minimally invasive approach to remove the 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] or 4-dimensional CT to localize the abnormal parathyroid gland);
    AND
  • Intraoperative measurement of iPTH (IOPTH) to ensure an adequate resection of all hyperfunctioning tissue.

IOPTH involves measurement of serum iPTH at the initiation of the surgery and again at five minutes and at 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 greater than 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.

If there is any suggestion of adherence of the parathyroid gland to the thyroid parenchyma, a concomitant thyroid lobectomy should be considered. In the past, prophylactic total parathyroidectomy was suggested to reduce the risk of parathyroid carcinoma in HPT-JT syndrome; however, given the difficulty in treating postsurgical hypoparathyroidism, this approach is not widely accepted.

In 2009 Iacobone et al evaluated 17 individuals with HPT-JT syndrome from three large families; 82% of individuals had single gland disease. These findings supported unilateral operation when preoperative imaging targeted the offending gland. Because the disease usually involves a single gland, a multigland resection increases the risk for hypoparathyroidism with no true benefit of reducing disease recurrence. Therefore, subtotal parathyroidectomy (the standard surgery in MEN1) is not recommended.

Mehta et al [2014] found that in their cohort of 16 individuals from seven families, 31% of individuals had multiglandular disease and 37.5% of individuals developed parathyroid carcinoma. These data were collected for individuals over three decades with variable preoperative imaging. This group recommended bilateral neck exploration to assess all four parathyroid glands and en bloc resection of parathyroid tumors in individuals with HPT-JT syndrome given the increased risk of multiglandular disease and malignancy.

Regardless of the surgical approach, the risk of recurrent and/or new metachronous 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, palpable cervical disease, and clear radiographic evidence of parathyroid neoplasia. In this situation, an en bloc resection including the ipsilateral thyroid lobe is indicated. Care to prevent fracture of the tumor, which could seed the local area and cause parathyromatosis, is critical. Experienced surgeons can usually distinguish typical benign parathyroid tissue from carcinoma. Benign tissue is peanut butter colored, 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-gray, large, and intimately attached to surrounding structures [Author, personal experience].

For severe or symptomatic hypercalcemia, individuals can be treated with an infusion of zoledronic acid or pamidronate for acute management. For long-term control of hypercalcemia that occurs in individuals who are unable to undergo parathyroidectomy and for the treatment of parathyroid carcinoma-related hypercalcemia, cinacalcet hydrochloride (Sensipar®), a calcimimetic that binds to the calcium-sensing receptor, can be used for medical management [Messa et al 2011]. Cinacalcet has proven effective in individuals with inoperable parathyroid carcinoma [Silverberg et al 2007] and has been used in an individual with CDC73-associated primary hyperparathyroidism for whom parathyroidectomy was considered high risk [Sato et al 2016].

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 individuals. There are no well-defined medical approaches to unresectable jaw tumors. Individuals with a history of jaw tumors 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 postsurgical hypoparathyroidism, this approach is not recommended.

Prevention of Secondary Complications

The risk of postoperative 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 individuals suspected of having parathyroid carcinoma in order to optimize a surgical cure and prevent positive surgical margins or seeding of parathyroid tissue (parathyromatosis) during removal.

Surveillance

There are currently no well-established surveillance guidelines for individuals with a CDC73-related disorder. Based on an extensive literature review, the following are recommended:

  • Annual serum 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) starting at age five years.
  • Individuals with a history of parathyroid carcinoma, who develop a rise in calcium levels, should be evaluated for a new primary parathyroid tumor or recurrence/progression of malignant disease.
  • Consider periodic parathyroid ultrasound examination for the detection of non-functioning parathyroid carcinoma.
  • Obtain panoramic x-ray dental imaging with neck shielding 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 a CDC73-related disorder 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.
  • Starting at reproductive age, women with a CDC73-related disorder should undergo regular gynecologic care (including pelvic examination). Care providers in obstetrics and gynecology should be notified of the risk of uterine tumors. Pelvic ultrasound examination should be obtained in any woman with a menstrual disorder (particularly abnormal uterine bleeding or menorrhagia) with further imaging studies (CT or MRI) as clinically indicated.

Agents/Circumstances to Avoid

The following should be avoided:

  • Dehydration
  • Radiation exposure
  • 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 beginning at age five years in order to identify as early as possible those who would benefit from initiation of surveillance, treatment, and/or preventive measures.

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.

See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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.

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

  • Some individuals with a CDC73-related disorder inherited a CDC73 pathogenic variant from an affected parent.
  • Alternatively, an affected individual may have the disorder as the result of a de novo CDC73 pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo CDC73 pathogenic variant (i.e., neither parent is known to be affected with a CDC73-related disorder).
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. In one reported case, an affected individual had an affected parent with somatic and germline mosaicism [Villablanca et al 2004].
  • The family history of some individuals diagnosed with a CDC73-related disorder may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected [Villablanca et al 2004].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected and/or is known to be heterozygous for the CDC73 pathogenic variant, the risk to the sibs is 50%. Age of onset, severity, type of symptoms, or rate of progression cannot be predicted in sibs who inherit a CDC73 pathogenic variant.
  • If the parents have been tested for the CDC73 pathogenic variant identified in the proband and the pathogenic variant was not detected in either parent's leukocyte DNA, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
  • The absence of clinical symptoms in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CDC73 pathogenic variant, 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 and Preimplantation Genetic Diagnosis

Once the CDC73 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CDC731q31​.2ParafibrominCDC73 databaseCDC73CDC73

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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

145000HYPERPARATHYROIDISM 1; HRPT1
145001HYPERPARATHYROIDISM 2 WITH JAW TUMORS; 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.

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

Pathogenic variants. More than 45 pathogenic sequence variants have been described for CDC73. Nonsense, missense, frameshift, and splice site variants as well as small deletions and insertions have been reported in individuals/pedigrees affected with hyperparathyroidism-jaw tumor (HPT-JT) syndrome [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, van der Tuin et al 2017].

Most pathogenic variants appear to be unique to individual families; however, some pathogenic variants have been found repeatedly in unrelated families [Cavaco et al 2004, Bradley et al 2005]. The c.766_767delGT variant in exon 8 appears to be a founder pathogenic variant in Roma families from Portugal [Cavaco et al 2004].

The importance of deletion/duplication analysis is highlighted in the study reported by Bricaire et al [2013], where seven of 20 probands were found to have whole-gene deletions. Furthermore, among 97 affected individuals in whom sequence analysis failed to identify a pathogenic variant, 7% (7/97) had deletion of one or more exons of CDC73 that were detected by deletion/duplication analysis. For other reports of gross deletions see Caron et al [2011], Cascón et al [2011], and Domingues et al [2012]. See also Table A, HGMD.

Table 2.

CDC73 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.131+1G>ANM_024529​.4
NP_078805​.3
c.679_680insAGp.Arg227LysfsTer31
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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

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 dinucleotide repeat of (AG)5, and several frameshift variants altering this motif have been reported. 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 CDC73 [Bradley et al 2006]. Parafibromin has also been shown to inhibit cell proliferation by repression of the c-myc proto-oncogene and mediate cyclin D1 repression through histone methylation, further supporting the role of CDC73 as a tumor suppressor [Woodard et al 2005, Lin et al 2008, Yang et al 2010].

Abnormal gene product. The pathogenicity of CDC73 whole-gene deletions indicates that inactivation of one allele and haploinsufficiency of parafibromin is the cause of the phenotype. This is consistent with the many reported germline CDC73 small deletions/insertions or nonsense pathogenic variants.

Cancer and Benign Tumors

Sporadic tumors (including parathyroid carcinoma, benign parathyroid tumors, and renal tumors) occurring as single tumors in the absence of any other findings of CDC73-related disorders frequently may harbor somatic variants in CDC73 that are not present in the germline. In these circumstances predisposition to these tumors is not heritable.

Parathyroid carcinoma. Somatic CDC73 pathogenic variants are associated with parathyroid carcinoma, but also occur uncommonly in sporadic benign parathyroid tumors [Howell et al 2003, Shattuck et al 2003, Cetani et al 2004, Krebs et al 2005]. Therefore, somatic variants of CDC73 have been implicated in malignant transformation of parathyroid tumors.

It has been suggested that presence of CDC73 somatic pathogenic variants and loss of parafibromin immunostaining could be used as markers of malignant potential in parathyroid neoplasms and 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, Kruijff et al 2014].

Renal tumors. 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].

Ossifying fibroma of the jaw. Heterozygous somatic CDC73 pathogenic variants were identified in two of 40 tumors studied from individuals with a sporadic ossifying jaw fibroma [Chen et al 2016].

References

Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 4-9-18. [PubMed: 23428972]
  • National Cancer Institute Statement: Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute). Available online. Accessed 4-9-18.
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 4-9-18.
  • Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70–87. [PubMed: 25394175]

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Chapter Notes

Author History

Maria E Cabanillas, MD; University of Texas, Houston (2008-2012)
Mimi I Hu, MD (2012-present)
Samuel M Hyde, MMSc, CGC (2018-present)
Michelle A Jackson, MS, CGC; University of Texas MD Anderson Cancer Center (2015-2018)
Jack W Martin, MD; University of Texas MD Anderson Cancer Center (2008-2015)
Nancy D Perrier, MD, FACS (2008-present)
Thereasa A Rich, MS, CGC (2008-present)
Steven G Waguespack, MD (2008-present)

Revision History

  • 26 April 2018 (sw) Comprehensive update posted live
  • 15 January 2015 (me) Comprehensive update posted live
  • 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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