Hyperparathyroidism-jaw Tumor Syndrome Research Articles

Lameness revealing primary hyperparathyroidism jaw-tumor syndrome (HPT-JT)!

Lameness revealing primary hyperparathyroidism jaw-tumor syndrome (HPT-JT)!

Insights into Hyperparathyroidism-Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours.

A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism-jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.

O-14 A rare case of hypercalcaemia in pregnancy

Abstract Introduction Hypercalcaemia is infrequent during pregnancy, but it is associated with foetal and maternal morbidity and mortality. Although primary hyperparathyroidism (pHPT) accounts for the majority of the cases, other aetiologies such as genetic causes in a young population should be considered. Clinical Case A 27-year-old female was diagnosed with pHPT during her 16th week of gestation after she presented with vomiting and was found to have raised adjusted calcium of 3.22 mmol/L, low phosphate of 0.6 mmol/L and Parathyroid Hormone of 10.6 pmol/L. The patient's hypercalcaemia dated back 2 years, she had a history of three previous miscarriages, and was not on any hypercalcaemia-inducing medications. Unbeknownst to her, her father was also being evaluated for hypercalcaemia. Her thyroid-stimulating hormone was fully suppressed with raised free thyroid hormones and negative TSH receptor antibodies; this was improved with Carbimazole therapy. Plasma and urine Metanephrines were normal, and neck ultrasound did not reveal any parathyroid lesions. She underwent parathyroidectomy three weeks later after a period of intravenous hydration. A 2 cm left superior parathyroid adenoma was excised, and the plasma calcium level promptly normalised. Genetic testing for familial hyperparathyroidism revealed an autosomal dominant heterozygous CDC73 variant, which is associated with Hyperparathyroidism-Jaw Tumour syndrome. The Clinical Genetics team is arranging genetic testing for her first-degree relatives. She delivered a live baby at 38 + 6 weeks of gestation via emergency caesarean section, performed for foetal hypoxia on cardiotocography, and genetic testing of the newborn child using umbilical cord blood was performed at the time of delivery. She will undergo regular screening for uterine, renal and jaw tumours (every 5 years), and is planned for 6-monthly calcium and parathyroid hormone tests. Conclusion Primary hyperparathyroidism is best treated with parathyroidectomy before pregnancy as the maternal and foetal complications increase according to the hypercalcaemia severity. During pregnancy, mild cases could be treated conservatively while parathyroidectomy is reserved for severe cases and is performed in the second trimester. Germline CDC73 analysis is recommended in young pHPT patients, and in this case revealed a pathological variant associated with Hyperparathyroidism-Jaw Tumour syndrome, familial isolated pHPT and parathyroid carcinoma.

O-13 Parathyroid carcinoma - a rare and challenging entity

Abstract Background Parathyroid carcinoma is a rare malignancy, accounting for less than 1% of all cases of primary hyperparathyroidism (HPT). This entity affects both men and women equally and is usually diagnosed in the fourth or fifth decade of life. It can occur sporadically or be associated with genetic syndromes such as hyperparathyroidism-jaw tumor syndrome. Its clinical presentation can overlap with that of primary HPT, with hypercalcemia that can lead to a range of symptoms, such as fatigue, weakness, bone pain, kidney stones, and gastrointestinal disorders. Distinguished by its rarity and clinical challenges, this condition requires a high level of suspicion and its initial surgical approach correlates with long-term prognosis. Clinical Case This is the case of a male patient, 39 years old, Caucasian, with a previous history of hypertension diagnosed 5 months earlier, deep vein thrombosis (DVT) diagnosed 2 months earlier, and active tobacco use. Additional study performed after the DVT episode found severe hypercalcemia (14.3 mg/dL, N 8.6-10.0), hypophosphatemia (2.2 mg/dL, N 2.5-4.5), and renal dysfunction (Creatinine 1.43 mg/dL). The patient was asymptomatic and was admitted to the Internal Medicine department, to correct the hypercalcemia and further investigation. Increased PTH levels (1555 pg/mL, N 15-65) were found, and a cervical ultrasound revealed, on the left thyroid lobe, a bilobed nodule, mainly solid, hypoechogenic, with irregular margins and macrocalcifications, with 34×22 mm. Full body CT showed osteolytic lesions on several ribs and both iliacs and kidney stones. A bone scintigraphy was also done, showing a diffuse fixation on the axial and appendicular skeleton, compatible with diffuse osteomedullary infiltration. Due to these findings, the collaboration of the Endocrinology department was requested. Based on the PTH levels and the characteristics of the cervical mass, suspicion arose regarding a potential case of parathyroid carcinoma. Subsequently, a parathyroid scintigraphy using Sestamibi was conducted, whose report revealed an intense hyperfixation at a nodular formation projecting on the lower two-thirds of the thyroid left lobe, without unequivocal identification of its origin - thyroid nodule vs. parathyroid tissue. Based on intraoperative findings and clinical suspicion, en bloc resection of the tumor along with the thyroid lobe and unilateral neck exploration was performed by the Surgery department, with the pathological assessment confirming the malignancy diagnosis. The patient was referred to an oncologic tertiary center, for follow-up and genetic testing. Conclusion We want to shed light on this rare entity and the importance of multidisciplinary critical thinking, alongside imaging. Markedly elevated PTH and/or calcium levels on a patient with a cervical mass should arouse suspicion of a parathyroid carcinoma, which must not be biopsied and warrants a more extensive surgery to ensure the best possible prognosis.

OBSTETRICAL AND NEONATAL OUTCOMES AMONG PREGNANCIES COMPLICATED BY HYPERPARATHYROIDISM: SYSTEMATIC REVIEW

Background: Primary hyperparathyroidism (PHPT) is a relatively common disorder of the parathyroid glands, causing skeletal, renal, and cardiac complications. As etiological features of PHPT, single adenoma, hyperplasia, carcinoma, and familiar causes (MEN multiple endocrine neoplasia, FHH familiar hypocalciuric hypercalcemia, hyperparathyroidismjaw tumor syndrome) are presented. Primary hyperparathyroidism in pregnancy has an incidence of 1, which is underestimated due to the plethora of undiagnosed cases.   The aim: This study aims to show about obstetrical and neonatal outcomes among pregnancies complicated by hyperparathyroidism. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2013 and 2023 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 10 articles, whereas the results of our search on SagePub brought up 60 articles. The results of the search conducted for the last year of 2013 yielded a total 2 articles for PubMed and 14 articles for SagePub. The result from title screening, a total 1 articles for PubMed and 10 articles for SagePub. In the end, we compiled a total of 7 papers. We included five research that met the criteria. Conclusion: Pregnancy complicated by PHPT may lead to serious maternal and infant complications. MDT consultation ensures timely diagnosis, comprehensive treatment for the patients and better pregnancy outcomes.

THU525 Atypical Presentation Of Parathyroid Carcinoma In The Lungs

Abstract Disclosure: J.N. Jacinto: None. O. Reyes: None. M. Cating-Cabral: None. R. Santiago: None. J. Andal: None. A 66-year-old female with a history of parathyroid adenoma underwent partial parathyroidectomy and thyroidectomy of the right lobe in 2006. She has the following comorbidities: pre-diabetes, hypertension, multiple liver cysts, medullary nephrocalcinosis and nephrolithiasis, ureterolithiasis and uterine intramural myoma. She also has a strong familial disposition of endocrine tumors. During the last quarter of 2018, parathyroid hormone and calcium levels were elevated and parathyroid imaging revealed an adenoma on the posteromedial aspect of the left thyroid lobe. Removal of the adenoma was offered but insisted on medical treatment. In 2022, she was admitted for subarachnoid hemorrhage due to fall. There was an incidental finding of a lung mass with minimal pleural effusion on the right lung lobe. PET-scan revealed five FDG-avid nodules (SUV up to 9.6) with the largest in the right middle lobe measuring 2 x 2 x 2 cm. Percutaneous needle biopsy was performed which showed a tumor with fairly uniform cells in organoid nests and solid clusters. By immunohistochemistry (IHC), the tumor cells were diffusely and strongly positive for CK and GATA-3; focally positive for chromogranin and synaptophysin; and negative for TTF-1, Pax-8, and S100. This was signed out as an epithelial tumor with neuroendocrine features; the differential diagnosis includes pulmonary neuroendocrine tumor versus metastasis from the prior parathyroid lesion. She subsequently underwent completion thyroidectomy and video-assisted thoracoscopic surgery. The lung wedge resections both showed tumors with similar morphology and IHC staining pattern as the biopsy. Additional stains were also performed to rule out other entities, which were all negative (CK7, CK20, CD56, mammaglobin, GCDFP-15, TTF-1, S100, ER, Pax-8, HSA, and SALL-4). The Ki-67 proliferation index was 17.26%. Because the overall findings were not definitive, comprehensive genomic profiling by next generation sequencing (NGS) was recommended and subsequently performed. NGS showed gene alteration in CDC73, with a variant allele frequency of 50%; this finding has been documented in parathyroid carcinoma. Pre-operative parathyroid hormone levels remained unchanged (408 to 397 pg/ml) despite surgery. Currently, there is no available targeted therapy to address her genomic alteration. Hyperparathyroidism-jaw tumor syndrome was entertained. The multidisciplinary team advised en-bloc resection of the lung tumor and additional gene testing for family members. She opted for palliative care and is on cinacalcet for her hyperparathyroidism. Presentation: Thursday, June 15, 2023

FRI686 Phenotypic Profiling And Molecular Mechanisms In Hyperparathyroidism-jaw Tumor Syndrome

Abstract Disclosure: R. Tora: None. J. Welch: None. J. Sun: None. S.K. Agarwal: None. D.A. Bell: None. M. Merino: None. L.S. Weinstein: None. W.F. Simonds: None. S. Jha: None. Background: Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism (PHPT) that is associated with tumors in the parathyroid, jaw, kidney, and uterus. We previously presented on the clinical characteristics of primary hyperparathyroidism in our cohort. Methods: We now expand on the report through review of uterine tumors, immunohistochemical staining for parafibromin, sequencing of parathyroid and kidney tumor tissue, and RNA-seq of parathyroid tumors. Results: We identified 68 patients (36 males, 32 females) from 29 kindreds with HPT-JT with median age at last follow-up of 39 [29-53] years. Of these, 7 patients were unaffected (2 males, 5 females). Among females, 12/32 (38%) developed uterine tumors with multiple adenomyomatous polyps, an unusual form of endometrial polyps seen in 10/24 tumors (42%). Given that these types of lesions are very rare in the general population, it is likely that such epithelial-mesenchymal uterine proliferations are a characteristic feature of HPT-JT syndrome.Solid kidney tumors were seen in 4/61 patients (7%). Three had surgery for the tumors - 2/3 were female and had mixed epithelial stromal tumor, while the third patient, a 6-year old male, had metastatic Wilm’s tumor as his initial disease-related manifestation. Among these, two had a germline CDC73 variant at the p.M1 residue while the third patient had the germline variant p.L95P; however, sequencing of his tumor tissue showed a “second hit” at the p.M1 residue resulting in loss of heterozygosity in the tumor. The fourth patient, a female with p.Y55S variant, is being conservatively managed with no kidney surgery yet. All three women with kidney tumors also had a history of uterine tumors. Parafibromin staining of 19 available CDC73 related parathyroid tumors (13 adenomas and 6 carcinoma) did not correlate with histology or genotype. Pathway analysis of 21 parathyroid tumors (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas and 7 sporadic parathyroid carcinoma with wild-type CDC73) showed a significant association of HPT-JT-related parathyroid carcinoma with growth, transmembrane receptor protein tyrosine kinase signaling and mesodermal commitment pathways. Conclusion: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be characteristic of HPT-JT syndrome. Our findings support germline testing at a young age in first-degree relatives of patients with HPT-JT given onset of manifestations as early as 6 years. Variants at M1 residue appear to predispose to genitourinary tumors. At present, there are no therapeutic approaches to compensate for CDC73 inactivation. Future research to identify standards of care and therapeutics targets are warranted for this rare disease. Presentation: Friday, June 16, 2023

SAT249 Femur Lysis Calcium Crisis

Abstract Disclosure: G. Gupta: None. S. Idriss: None. N. Barua: None. J. Hodge: None. I. Jamal: None. Introduction: Primary hyperparathyroidism usually presents with symptoms of bone pain, fatigue, polyuria, constipation, and nephrolithiasis. Here we describe a 27-year-old female with a femoral neck fracture and found to have a parathyroid mass. Case: 27 y/o female with autism spectrum, presented to the ED for evaluation of a mechanical fall and was found to have a left femur and pubic ramus fracture. On arrival she was vitally stable, labs were significant for parathyroid hormone-related hypercalcemia corrected Ca 14.8 mg/dL, PTH 911 peaked to 2884 pg/mL, vit D level of 12.7 ng/mL, phosphorus of 2.3 mg/dL. Trauma workup revealed numerous osseous lytic lesions lower extremities. Review of system was negative except for localized pain at fracture site. Family history negative for hypercalcemia or hyperparathyroidism. She was managed with IV fluids, IV Zoledronic Acid 4 mg, SC calcitonin 240 units, and 50K IU D3. During hospitalization, she needed re-dozing with Zoledronic acid and Cinacalcet due to recurrence of significant hypercalcemia, warranting further imaging. CT neck showed mandibular and maxillary bone lesions raising suspicion of hyperparathyroidism jaw tumor syndrome (HPT-JT) vs brown tumors, 3.1 cm lobular mass inferior to the right thyroid lobe suspicious for large parathyroid adenoma vs carcinoma, and other multiple enlarged parathyroids. She underwent left femur cephalomedullary nailing and prophylactic nailing for the impending right femur fracture. Bone pathology showed fragmented bone, adipose, and skeletal muscle with fibrinous debris. She underwent subtotal parathyroidectomy (4-1/2 glands) and intraoperative PTH level declined from 1537 to 75 pg/mL 15 minutes after removal. Pathology showed tissue consistent with multi glandular parathyroid disease without evidence of malignancy. Postop her course was complicated with hungry bone syndrome requiring a few weeks on IV calcium. Discussion: Pathologic conditions in primary hyperparathyroidism include single adenomas (80-90% of the time), multiglandular hyperplasia multiple-gland (three or more glands) accounting for approximately 6%, and parathyroid carcinomas account for 1-2% of cases. Other conditions as with primary hyperparathyroidism include Familial hyperparathyroidism such as MEN 1 & 2A, Familial isolated hyperparathyroidism, and Familial HPT-JT syndrome, previously termed familial cystic parathyroid adenomatosis. Interestingly our pt had multiglandular hyperplasia which is a less common cause, she also demonstrated jaw lesions but didn’t fulfill the criteria for HPT-JT. Conclusion: Our patient had an unusual presentation of large bone fracture and multiple lytic lesions likely representing a brown tumor of the bone due to primary hyperparathyroidism. Most patients with lytic lesions have malignancy, however, endocrine pathologies should also be considered. Presentation: Saturday, June 17, 2023

THU404 Classical Symptoms Masquerading As A Surprising Clinical Picture

Abstract Disclosure: A. Syal: None. Y. Arya: None. S. Teja Sathi: None. J. Prater: None. Introduction: Primary hyperparathyroidism commonly presents in the setting of a parathyroid adenoma or hyperplasia, although it can rarely be caused parathyroid carcinoma, often accounting for <1% of cases. Markedly elevated PTH levels, along with predominant uniglandular involvement should increase the suspicion of an underlying parathyroid carcinoma, given that multiglandular involvement is rarely encountered. Surgical resection with histopathological confirmation remains the mainstay of diagnosis. Case presentation: We describe the case of a female in her late 50s who was brought to the emergency department by her family with complaints of altered mental status, hallucinations, delusions, anxiety, increased urination, constipation, and decreased appetite for the past month. Her laboratory evaluation was significant for hypercalcemia with a corrected calcium of 13.4 mg/dL. She was started on intravenous fluids and calcitonin, with improvement in her clinical condition. Further workup for her hypercalcemia revealed that the serum parathyroid hormone (PTH) was significantly elevated at 1846.4 pg/mL (normal low: 9, normal high: 73). Her serum phosphorus was low, and 25-hydroxy vitamin D was high-normal. This was consistent with a picture of primary hyperparathyroidism. The severely elevated PTH raised concern for parathyroid carcinoma, a rare clinical entity. The patient underwent a nuclear medicine parathyroid scan (technetium 99m sestamibi), which revealed abnormal focal uptake in the inferior right thyroid bed. Ultrasound of the neck revealed a hypoechoic avascular nodule inferior to the right thyroid lobe corresponding to the area of increased sestamibi activity on nuclear medicine scan. After much discussion with the patient’s family, surgical intervention was deferred to a later date, with a focus on stabilization in the acute setting. The patient was started on cinacalcet for her hypercalcemia. Bisphosphonates were initially held in anticipation for surgery but were eventually started. Discussion: Parathyroid carcinoma is a rare malignancy, which can occur both sporadically and as part of the hereditary hyperparathyroidism-jaw tumor syndrome. In clinical practice, subtle clues which increase the suspicion for a parathyroid carcinoma include severely elevated PTH, sometimes up to 10 times the upper limit of normal, increasing adenoma size, and a presentation outside of the commonly inherited MEN-1 syndromes.[1] We rely solely on post-operative pathology to establish the diagnosis of parathyroid carcinoma, given that there are no well-defined features or criteria that can establish the diagnosis on imaging.

FRI692 Severe Hyperparathyroidism And Nephrolithiasis In An Adolescent Male Due To CDC73 Positive Parathyroid Carcinoma

Abstract Disclosure: J.T. Nguyen: None. D.H. Geller: None. A. Ryabets-Lienhard: None. Introduction: Parathyroid carcinoma is a rare cause of primary hyperparathyroidism in the pediatric population, with only 20 previously reported cases. Variations in the CDC73 gene have been associated with sporadic parathyroid carcinoma, autosomal dominant hyperparathyroidism-jaw tumor syndrome (HPT-JT), and familial isolated hyperparathyroidism (FIHP). To our knowledge, only 3 cases of pediatric parathyroid carcinoma with confirmed variants of CDC73 have been reported. We present a case of severe hyperparathyroidism and nephrolithiasis due to parathyroid carcinoma caused by a pathogenic variant in CDC73 in a pediatric patient, highlighting the importance of early recognition and management. Clinical Case: An otherwise asymptomatic 14-year-old male presented with one year of recurrent nephrolithiasis. Initial tests demonstrated hypercalcemia (13.8 mg/dL, 8.4-10.2 mg/dL), normal phosphorous, elevated PTH (1,379 pg/mL, 7.5-53.5 pg/mL), and elevated alkaline phosphatase (514 U/L, 30-250 U/L). The hypercalcemia was treated with hyperhydration, furosemide, and pamidronate. Sestamibi scan revealed a focus of abnormal uptake suggestive of a left parathyroid mass, with ultrasonographic demonstration of a predominantly solid, hypoechoic, and vascular mass centered posterior to the inferior left thyroid lobe. Skeletal survey was notable for trabecular abnormalities and osteopenia. He underwent a left parathyroid mass excision. Final pathology confirmed the parathyroid carcinoma, with multiple foci of vascular invasion without evidence of capsular involvement. Immunohistochemistry demonstrated diffuse positivity for PTH and loss of parafibromin expression by the tumor cells. Genetic testing revealed a pathogenic germline heterozygous nonsense variant in CDC73 (c.376C>T(p.Arg126Ter)) resulting in protein truncation. Post-operative PTH was undetectable with normal calcium and phosphorous. Calcitriol, cholecalciferol, and calcium carbonate supplementation were implemented to prevent further hypocalcemia due to transient hypoparathyroidism and hungry bone syndrome. Calcium supplementation was discontinued within one year of his surgery. Serial thyroid ultrasounds and CT scans have been negative for recurrent or residual disease without evidence of metastasis. Mandibular x-ray showed no evidence of tumors or lesions involving the jaw. He has been noted to have small right renal cysts without other kidney abnormalities. Conclusion: Severe hyperparathyroidism due to parathyroid carcinoma can present as recurrent nephrolithiasis in an otherwise asymptomatic individual. Pediatric patients with a longstanding history of kidney stones should undergo screening for hypercalcemia and hyperparathyroidism even in the absence of other signs and symptoms of elevated calcium to ensure timely diagnosis and appropriate management. Presentation: Friday, June 16, 2023

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. NCT04969926.

A rare case of Hyperparathyroidism Jaw Tumour Syndrome without jaw tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Hyperparathyroidism Jaw Tumour Syndrome in Pregnancy: A rare coexistence

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The clinicopathological and prognostic significances of CDC73 expression in breast cancer: A pathological and bioinformatics analysis.

Parafibromin is a protein encoded by the oncosuppressor CDC73 gene, whose mutation results in hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid carcinoma. Down-regulation of parafibromin is linked to lung, gastric, colorectal, and ovarian cancer tumorigenesis. Parafibromin expression was detected by RT-PCR, bioinformatics analysis, Western blot, and immunohistochemistry; and compared with clinicopathological characteristics of breast cancer. CDC73-related genes and pathways were analyzed using bioinformatics analysis. Parafibromin expression was increased in breast cancer compared to normal tissues at both mRNA and protein levels (p<0.05). Among triple-negative breast cancers, it was higher in basal-like 1 than basal-like 2 patients (p<0.05) and mesenchymal than immunomodulatory patients (p<0.05). CDC73 mRNA expression was positively correlated with white race, non-infiltrating immune cells, favorable luminal subtypes of PAM50, and prognosis of breast cancer patients (p<0.05). The differential genes of CDC73 were classified into enzyme inhibitors, peptidase, and keratinization by KEGG (p<0.05). Similarly, it was classified into ribosomes, TGF-β, oxidation phosphorylation, inositol phosphate metabolism, arachidonic acid metabolism, linoleic acid metabolism, ERBB, and VEGF signaling pathways by GSEA (p<0.05). The positively-correlated genes of CDC73 were involved in cell mobility, response to interferon α, nuclear pore and basket, and histone methyltransferase. The negatively-correlated genes of CDC73 were involved in the mitochondrial respiratory chain, thermogenesis, and ribosomes. Parafibromin expression was higher in invasive ductal than lobular carcinoma (p<0.05) and mucinous adenocarcinoma than others (p<0.05). Parafibromin immunoreactivity as an independent factor was positively associated with an increased overall survival rate of breast cancer patients (p<0.05). These findings suggest that up-regulation of parafibromin in breast cancer patients is closely linked to a favorable prognosis. It is involved in tumorigenesis and subsequent progression by regulating metabolism, ribosomes, and cytokines.

Hyperparathyroidism-jaw tumor syndrome: A rare disorder with significant clinical features

Hyperparathyroidism-jaw tumor syndrome: A rare disorder with significant clinical features

Familial parathyroid tumours-comparison of clinical profiles between syndromes.

Primary hyperparathyroidism (PHPT) caused by parathyroid tumours is mostly sporadic, with a genetic cause identified in 5-10% of cases. Familial parathyroid tumours can be included in complex syndromes, such as multiple endocrine neoplasia (MEN) type 1, 2A and 4 or hyperparathyroidism-jaw tumour syndrome (HPT-JT). Characterisation of the familial parathyroid tumours followed-up at our centre and comparison of the different clinicopathological manifestations between the syndromes. Retrospective analysis of 48 patients with familial parathyroid tumours harbouring RET (n = 11), CDC73 (n = 20) and MEN1 (n = 17) germline mutations was performed. Cases of PHPT in MEN2A syndrome presented with lower serum PTH (sPTH) and serum calcium (sCa) levels at diagnosis (sPTH = 108.0 (IQR 53.3) pg/mL, sCa = 10.6 ± 1.1mg/dL) than MEN1 (sPTH = 196.9 (IQR 210.5) pg/mL, sCa = 11.7 ± 1.2mg/dL) (p = 0.01, p = 0.03, respectively) or HPT-JT cases (sPTH = 383.5 (IQR 775.8) pg/mL, sCa = 12.9 ± 1.8mg/dL) (p = 0.01; p < 0.001, respectively). There was a statistical difference in sCa levels between MEN1 and HPT-JT (p = 0.02), but not between sPTH (p = 0.07). The predominant first manifestation of the syndrome in MEN1 was gastroenteropancreatic neuroendocrine tumour (GEP-NET) in 47.1% of the cases, in MEN2A was medullary thyroid cancer (90.9%) and in HPT-JT was PHPT in 85% patients. In MEN1 syndrome, the number of affected parathyroid glands was significantly higher than in MEN2A (p < 0.001) and HPT-JT (p = 0.01). The first manifestation of the syndrome in MEN1 cases was GEP-NET and not PHPT. Although presenting at similar ages, patients with MEN2A exhibit less severe biochemical and clinical PHPT at diagnosis than the other familial syndromes.

Hyperparathyroidism jaw tumour syndrome due to a novel familial CDC73 germline mutation

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A two-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family: clinical presentations, pathological characteristics and genetic analysis: a case report

BackgroundHyperparathyroidism-Jaw Tumor (HPT-JT) is caused by inactivating germline mutations of CDC73. This hereditary disease can present with a range of symptoms. Jaw ossifying fibroma (OF) is one of the most important clinical presentations, affecting 30% of HPT-JT patients. However, OF is easily confused with other fibro-osseous lesions (FOLs) of the jaw. The correct diagnosis of HPT-JT is a real challenge and must be confirmed by genetic testing.Case presentationA female proband and her father suffered from multiple and recurrent FOLs in the jaw. Considering well demarcated margin and heterogeneous calcified substance lying in a variable density of fibrous stroma, we reached the diagnosis of jaw OF through radiologic and microscopic analyses. Additionally, the proband presented with chronic anemia resulting from menorrhagia, as well as renal mixed epithelial and stromal tumor (MEST). Two patients both presented with no evidence of Hyperparathyroidism (HPT). A germline start codon mutation (c.1A > G) of CDC73 was identified in them. Copy number loss at the CDC73 gene locus was verified in the jaw tumor sample of the proband.ConclusionRegardless of whether HPT manifestations are present, patients with heritable jaw OF may be at risk for HPT-JT. Genetic testing should be adopted to confirm the diagnosis. Early recognition of HPT-JT helps to better develop tailored treatment plans and surveillance programs.

The roles of the tumor suppressor parafibromin in cancer.

In this review, we discuss parafibromin protein, which is encoded by CDC73. A mutation in this gene causes hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disease. CDC73 is transcriptionally downregulated by the Wilms’ tumor suppressor gene WT1 and translationally targeted by miR-182-3p and miR-155. In the nucleus, parafibromin binds to RNA polymerase II and PAF1 complex for transcription. Parafibromin transcriptionally increases the expression of c-Myc, decreases CPEB1 expression by interacting with H3M4, and reduces cyclin D1 expression by binding to H3K9. The RNF20/RNF40/parafibromin complex induces monoubiquitination of H2B-K120, and SHP2-mediated dephosphorylation of parafibromin promotes the parafibromin/β-catenin interaction and induces the expression of Wnt target genes, which is blocked by PTK6-medidated phosphorylation. Parafibromin physically associates with the CPSF and CstF complexes that are essential for INTS6 mRNA maturation. In the cytosol, parafibromin binds to hSki8 and eEF1Bγ for the destabilization of p53 mRNA, to JAK1/2-STAT1 for STAT1 phosphorylation, and to actinin-2/3 to bundle/cross-link actin filaments. Mice with CDC73 knockout in the parathyroid develop parathyroid and uterine tumors and are used as a model for HPT-JT syndrome. Conditional deletion of CDC73 in mesenchymal progenitors results in embryos with agenesis of the heart and liver while its abrogation in mature osteoblasts and osteocytes increases cortical and trabecular bone. Heterozygous germline mutations in CDC73 are associated with parathyroid carcinogenesis. The rates of CDC73 mutation and parafibromin loss decrease from parathyroid adenoma to atypical adenoma to carcinoma. In addition, down-regulated parafibromin is closely linked to the tumorigenesis, subsequent progression, or poor prognosis of head and neck, gastric, lung, colorectal, and ovarian cancers, and its overexpression might reverse the aggressiveness of these cancer cells. Therefore, parafibromin might be useful as a biological marker of malignancies and a target for their gene therapy.

USP37 Deubiquitinates CDC73 in HPT-JT Syndrome

The CDC73/HRPT2 gene, a defect which causes hyperparathyroidism–jaw tumor (HPT-JT) syndrome, encodes CDC73/parafibromin. We aimed to investigate whether CDC73 would be a target for ubiquitin–proteasome degradation. We cloned full-length cDNAs encoding a family of 58 ubiquitin-specific deubiquitinating enzymes (DUBs), also known as ubiquitin-specific proteases (USPs). Use of the yeast two-hybrid system then enabled us to identify USP37 as interacting with CDC73. The biochemical interaction between the USP37 and CDC73 and their reciprocal binding domains were studied. Co-localization of CDC73 and USP37 was observed in cells. CDC73 was found to be polyubiquitinated, and polyubiquitination of CDC73 was prominent in mutants. CDC73 was deubiquitinated via K48-specific ubiquitin chains by USP37, but not by the catalytically inactive USP37C350S mutant. Observation of the binding between deletion mutants of CDC73 and USP37 revealed that the β-catenin binding site of CDC73 and the ubiquitin-interacting motifs 2 and 3 (UIM2 and 3) of USP37 were responsible for the interaction between the two proteins. Moreover, these two enzymes co-existed within the nucleus of COS7 cells. We conclude that USP37 is a DUB for CDC73 and that the two proteins interact through specific domains, suggesting that USP37 is responsible for the stability of CDC73 in HPT-JT syndrome.