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]. Nonfunctioning 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.