Hyperparathyroidism-jaw Tumor Syndrome Research Articles

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.

Expression of Beta-Catenin, Cadherins and P-Runx2 in Fibro-Osseous Lesions of the Jaw: Tissue Microarray Study.

Fibrous dysplasia (FD) and hyperparathyroidism-jaw tumor syndrome (HPT-JT) are well-characterized benign bone fibro-osseous lesions. The intracellular mechanism leading to excessive deposition of fibrous tissue and alteration of differentiation processes leading to osteomalacia have not yet been fully clarified. Tissue Microarray (TMA)-based immunohistochemical expression of β-catenin, CK-AE1/AE3, Ki-67, cadherins and P-Runx2 were analyzed in archival samples from nine patients affected by FD and HPT-JT and in seven controls, with the aim of elucidating the contribution of these molecules (β-catenin, cadherins and P-Runx2) in the osteoblast differentiation pathway. β-catenin was strongly upregulated in FD, showing a hyper-cellulated pattern, while it was faintly expressed in bone tumors associated with HPT-JT. Furthermore, the loss of expression of OB-cadherin in osteoblast lineage in FD was accompanied by N-cadherin and P-cadherin upregulation (p < 0.05), while E-cadherin showed a minor role in these pathological processes. P-Runx2 showed over-expression in six out of eight cases of FD and stained moderately positive in the rimming lining osteoblasts in HPT-JT syndrome. β-catenin plays a central role in fibrous tissue proliferation and accompanies the lack of differentiation of osteoblast precursors in mature osteoblasts in FD. The study showed that the combined evaluation of the histological characteristics and the histochemical and immunohistochemical profile of key molecules involved in osteoblast differentiation are useful in the diagnosis, classification and therapeutic management of fibrous-osseous lesions.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Familial Tumor Syndromes.

The initiative of the 5th edition of the WHO classification of the Head and Neck Tumours establishing a new section dedicated to familial/heritable tumor syndromes with tumors and lesions in the head and neck region was much needed to better understand the tumours, diseases, and associated syndromes, as well as establish recommendations for monitoring and treating these patients. (WHO Classification of Tumours Editorial Board. Head and Neck tumours. Lyon (France): International Agency for Research on Cancer; 2022. https://publications.iarc.fr/ ). Within the newly established chapter on genetic tumor syndromes, we have described the main manifestations on the head and neck region in 15 syndromes. This review highlights the important findings within these syndromes, especially on the update on syndromes with tumors involving the head and neck region, as Gorlin syndrome/nevoid basal cell carcinoma syndrome associated with odontogenic keratocysts; Brooke-Spiegler syndrome/familial cylindromatosis and the associated membranous-type salivary gland basal cell adenoma, PTEN hamartoma tumor syndrome/Cowden syndrome with associated facial skin and mucosal lesions and characteristic multinodular thyroid lesions, Von Hippel Lindau syndrome and the associated middle ear endolymphatic sac tumor, as well as the fascinating genetic aspects of the diverse Head and Neck Paragangliomas. We will also discuss hyperparathyroidism-jaw tumor syndrome is characterized by parathyroid tumors in association with fibro-osseous jaw tumors, as well as head and neck desmoid tumors associated with familial adenomatous polyposis with Gardner syndrome variant familial, multicentric head and neck squamous cell carcinoma, tuberous sclerosis and neurofibromatosis type 1-associated head and neck lesions.

Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome.

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.

Renal Neoplasia in Hyperparathyroidism–Jaw Tumor Syndrome

A male patient in his late teens presented with primary hyperparathyroidism and underwent a parathyroidectomy. Germline testing revealed a pathogenic truncating alteration of the CDC73 gene (c.25C>T; p.Arg9Ter). On the basis of these findings, he was diagnosed with hyperparathyroidism–jaw tumor syndrome. In addition, multiple first-degree family members including his father and brother were found to have this syndrome. Approximately 2 decades later, he was found to have a 1.1-cm left renal mass on routine surveillance imaging. This was treated with a partial nephrectomy, and representative images of the renal tumor (hematoxylin and eosin stain, magnification ×100) are shown in Figure 1. This tumor showed a combination of papillary and nested architecture and exhibited inconspicuous nucleoli (World Health Organization grade 1). No recurrences or metastases were identified at 154 months of follow-up. What immunohistochemistry-based marker can be used to screen for tumors arising secondary to hyperparathyroidism–jaw tumor syndrome and what is the expected pattern of expression?a.Calcitonin, loss of stainingb.Parathormone, loss of stainingc.Parafibromin, loss of stainingd.Parafibromin, diffuse overexpression Answer: c Hyperparathyroidism–jaw tumor syndrome is inherited in an autosomal dominant manner secondary to pathogenic mutations of the CDC73 gene.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar Specifically, the pathogenic CDC73 c.25C>T, p.Arg9Ter alteration has been reported in both the somatic and germline setting.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar,2Cetani F. Pardi E. Borsari S. et al.Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors.J Clin Endocrinol Metab. 2004; 89: 5583-5591Crossref PubMed Scopus (189) Google Scholar These patients typically present with primary hyperparathyroidism secondary to parathyroid tumors, and in a subset of these patients, ossifying fibromas of the maxilla and mandible develop.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar Renal manifestations in this syndrome include cysts, hamartomas, metanephric adenoma, and Wilms tumor.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar,3Carlo M.I. Hakimi A.A. Stewart G.D. et al.Familial kidney cancer: implications of new syndromes and molecular insights.Eur Urol. 2019; 76: 754-764Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,4Gupta S. Vanderbilt C.M. Leibovich B.C. et al.Secondary renal neoplasia following chemotherapy or radiation in pediatric patients.Hum Pathol. 2020; 103: 1-13Crossref PubMed Scopus (5) Google Scholar The spectrum of renal neoplasia in hyperparathyroidism–jaw tumor syndrome is poorly defined because of the rarity of these tumors and limited reports of detailed histopathologic findings.3Carlo M.I. Hakimi A.A. Stewart G.D. et al.Familial kidney cancer: implications of new syndromes and molecular insights.Eur Urol. 2019; 76: 754-764Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,4Gupta S. Vanderbilt C.M. Leibovich B.C. et al.Secondary renal neoplasia following chemotherapy or radiation in pediatric patients.Hum Pathol. 2020; 103: 1-13Crossref PubMed Scopus (5) Google Scholar As the CDC73 gene encodes the parafibromin protein, immunohistochemistry for parafibromin has been proposed as a screening tool for tumors occurring in the context of hyperparathyroidism–jaw tumor syndrome.5Andrici J. Gill A.J. Hornick J.L. Next generation immunohistochemistry: emerging substitutes to genetic testing?.Semin Diagn Pathol. 2018; 35: 161-169Crossref PubMed Scopus (17) Google Scholar Loss of nuclear expression of parafibromin is thought to correlate with pathogenic loss of function alterations of CDC73 and has been proposed as an immunohistochemistry-based screening tool.5Andrici J. Gill A.J. Hornick J.L. Next generation immunohistochemistry: emerging substitutes to genetic testing?.Semin Diagn Pathol. 2018; 35: 161-169Crossref PubMed Scopus (17) Google Scholar This renal tumor exhibited papillary and nested architecture and a cytokeratin 7–positive immunophenotype (Figure 2A-C). Immunohistochemistry for parafibromin showed loss of nuclear expression in tumor cells, in contrast to retained expression in non-neoplastic vascular elements (Figure 2D). In addition to the patient described herein, loss of parafibromin expression has been reported in metachronous renal tumors (metanephric adenomas) for at least 1 other patient with this syndrome.4Gupta S. Vanderbilt C.M. Leibovich B.C. et al.Secondary renal neoplasia following chemotherapy or radiation in pediatric patients.Hum Pathol. 2020; 103: 1-13Crossref PubMed Scopus (5) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT)

Fibroma cementoossificante bilateral mandibular apresentando diferentes estágios de maturação: relato de caso clínico / Bilateral ossifying fibroma of the jaw with different maturation stages: a case report

The ossifying fibroma (OF) is characterized as a benign neoplasm originated from the mesenchymal periodontal membrane, being composed of different amounts of mineralized material and fibrocellular stroma, leading to a mixed aspect. More commonly found as solitary lesions, the OF can be multiple in rare cases, normally associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). The aim of this study is to report a case of bilateral OF in the mandible with different stages of maturation, not associated with HPT-JT. This case shows a 20-year-old female patient with asymptomatic intraoral hard swelling in both sides of the mandible, presenting a slight expansion in the buccal bone cortex, near to the molars, hard to palpation. CBCT showed a unilocular, well-circumscribed hypodense image, with calcified masses only on the right side. Incisional biopsies were performed and a diagnosis of bilateral OF was reached. Due to the different stages of maturation of the lesions, two different surgical approaches were performed, curettage in the left side and surgical resection in the right side with extraction of the lower second premolar and lower first molar. These areas were restored with bone grafts and the left first molar was unresponsive to the pulp vitality test and endodontic treatment was performed. The patient is undergoing periodic clinical and radiographic follow-up, and after 12 months no signs or evidence of recurrence were observed.

Parathyroid Carcinoma: a Review.

Parathyroid cancer is a rare endocrine malignancy with only a few thousand cases reported worldwide. As a result, there exists considerable controversy regarding the various aspects of this disease, viz., etiology, diagnosis, and management. We hereby attempt to review the literature on parathyroid carcinoma (PC) and summarize the practices based on the current evidence available. The majority of the PC are sporadic although an association with hyperparathyroidism-jaw tumor syndrome, multiple endocrine neoplasia (MEN) 1 and 2, and isolated familial hyperparathyroidism has been shown. As preoperative diagnosis is challenging, PC should be suspected in patients presenting with a neck mass with signs and symptoms of invasion to surrounding structures. Skeletal and renal symptoms are often associated with PC as presenting complaints. The biochemical parameters are more pronounced in the case of PC compared with benign countpart. Due to its rarity, the American Joint Committee of cancer control (AJCC) acknowledges that as yet a clear distinct staging system to prognosticate the disease would be premature. Complete excision with negative margins at first surgery offers the best chance of cure. The role of radiotherapy (RT) is still unclear; however few series have suggested a better locoregional control with adjuvant RT. Recurrences are common and are most significantly associated with an incomplete clearance at initial surgery. Surgical salvage of recurrent/metastatic disease with medical management of hypercalcemia is the treatment of choice. Large prospective studies and trials need to be conducted to understand the pathology better and improve management protocols; however this is a challenge due to rarity of cases.

The Unforeseen Diagnosis: Hyperparathyroidism-Jaw Tumour Syndrome Case Report and Review of the Literature

Hypercalcaemia and its systemic sequelae are a relatively common finding amongst patients in the field of endocrinology. Primary hyperparathyroidism, a frequent cause of hypercalcaemia, is often seen among middle-aged female patients, typically resulting from an underlying single-gland adenoma. Although patients may present with symptoms (nephrolithiasis, musculoskeletal discomfort, dehydration, or mood disturbance, to name a few), hypercalcaemia is rather frequently identified incidentally. In younger patients, a familial form of primary hyperparathyroidism must be considered, with a positive diagnosis mandating familial screening. Hyperparathyroidism-jaw tumour syndrome is one such autosomal dominant familial disorder, characterised by a mutation in the cell division cycle 73 (CDC73; also known as HRPT-2) tumour suppressor gene. This disorder is characterised by multiple pleiotropic phenomena, including recurrent primary hyperparathyroidism (and the effects of hypercalcaemia), neoplasms (such as uterine, renal, mandibular, and maxillary), and infertility. A patient not conforming to the classic candidacy for primary hyperparathyroidism requires consideration for a familial cause. Case Description. We present a rare diagnostic entity—hyperparathyroidism-jaw tumour (HPT-JT) syndrome—in a 36-year-old female with recurrent primary hyperparathyroidism, frequent nephrolithiasis, and infertility for 18 years prior to the diagnosis. We aim to promote awareness amongst medical professionals of this rare, but nonetheless essential differential diagnosis through a case report and review of the literature. Conclusion. Medical professionals must avoid diagnostic overshadowing and display a low threshold for genetic testing in younger patients with primary hyperparathyroidism. The importance of proper identification extends beyond the patient to their relatives and offspring.

Parafibromin Abnormalities in Ossifying Fibroma.

Ossifying fibromas are very rare tumors that are sometimes seen as part of the hyperparathyroidism-jaw tumor syndrome (HPT-JT), which is caused by inactivating mutations of the HRPT2/CDC73 tumor suppressor gene. CDC73 mutations have been identified in a subset of sporadic cases but aberrant expression of the encoded protein, parafibromin, has not been demonstrated in ossifying fibroma. We sought to determine if loss of parafibromin regularly contributes to the development of sporadic, nonsyndromic ossifying fibroma. We examined a series of 9 ossifying fibromas, including ossifying, cemento-ossifying, and juvenile active variants, for parafibromin protein expression by immunohistochemistry and for CDC73 sequence abnormalities by Sanger sequencing and/or targeted AmpliSeq panel sequencing. Four ossifying fibromas showed a complete absence of nuclear parafibromin expression; loss of parafibromin expression was coupled with aberrant cytoplasmic parafibromin expression in 1 case. CDC73 mutations were detected in 2 cases with aberrant parafibromin expression. These results provide novel evidence, at the level of protein expression, that loss of the parathyroid CDC73/parafibromin tumor suppressor may play a role in the pathogenesis of a subset of ossifying fibromas.

Hyperparathyroidism-Jaw Tumor Syndrome in a Patient With Colon Cancer: A Case Report

Abstract Background: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disease, caused by mutations in the CDC73 gene, characterized by parathyroid tumors in association with fibro-osseous lesions of the mandible or maxilla. The occurrence of renal cysts or tumors, uterine and thyroid tumors has been reported. The association with other neoplastic lesions has been described, but its meaning and frequency are not well established. Clinical Case: A 48-year-old Roma woman was admitted to our hospital due to severe abdominal pain and constipation. She had a past history of kidney stones with several episodes of acute renal colic and had been recently diagnosed with colon cancer. Her family history was positive for colon cancer. Disease staging suggested the presence of liver metastases and multiple lytic lesions of the axial skeleton, pelvis and femurs. Laboratory investigation disclosed high calcium levels (15 mg/dL) and cancer associated hypercalcemia was suspected. However, PTH was markedly elevated (2979 pg/mL), in favor of a parathormone dependent cause. Further imaging procedures showed a heterogeneous mass, posterior to the right thyroid lobe and bone lesions on the left mandible, likely to correspond to brown tumors. Once the hypercalcemia was controlled, she was submitted to parathyroidectomy and right thyroid lobectomy plus sigmoidectomy and liver biopsy. The histology revealed an atypical parathyroid adenoma with 3,5 cm and papillary thyroid cancer with 1,2 cm, as well as colon adenocarcinoma metastatic to the liver. Postoperatively, the patient developed a hungry bone syndrome needing adequate treatment. Two months after surgery, the patient initiated chemotherapy for colon cancer. Screening for germline mutations in the CDC73 gene (formerly HRPT2) was positive for a deletion (c.765_766delTG/p.Val256LysX10). Conclusions: Hypercalcemia in a patient with malignant disease may be independent of malignancy. In the patient presented herein her past history of kidney stones and the involvement of the mandible were highly suggestive of HPT-JT. Missing the diagnosis would negatively impact in the patient′s prognosis and in the management of her family. Further clinical and genetic studies are ongoing trying to clarify whether the patient has two inherited conditions or a phenotype of HPT-JT including colon cancer.

A Case Report on Parathyroid Carcinoma - an Extremely Rare Endocrine Malignancy

Abstract Background: Parathyroid carcinoma is an extremely rare endocrine malignancy with a prevalence of &amp;It 1%. It is associated with hyperparathyroidism-jaw tumor syndrome (HJTS), multiple endocrine neoplasia (MEN) type 1 or 2A syndromes, secondary hyperparathyroidism, and chronic kidney disease. Incidence is equal in both men and women. Patients may present with symptoms of hypercalcemia, and should be further worked up with neck ultrasound, Tc-99m sestamibi imaging, single-photon emission computed tomography, magnetic resonance imaging, positron emission tomography combined with CT scan, and biopsy of the parathyroid mass. Parathyroid carcinoma can be treated surgically with complete resection. Patients treated with En-bloc resection with microscopically negative margins remain cancer-free for at least three years to a maximum of twenty years. Case Report: A 50-year-old female treated with laparoscopic sleeve gastrectomy for morbid obesity, came for the follow-up visit. She denied any active complaint. Routine Lab work showed mild hypercalcemia, hypophosphatemia, elevated PTH, and alkaline phosphatase. Neck ultrasound showed a cystic lesion adjacent to the right thyroid lobe. Sestamibi (MIBI) parathyroid scintigraphy showed increased radiopharmaceutical uptake by the right superior parathyroid gland without any enlarged or suspicious lymph nodes. Dexa scan was positive for osteopenia. The patient underwent right superior parathyroidectomy along with en-bloc right thyroid lobectomy. Histological examination revealed anaplastic regions, giant cells with abundant cytoplasm, and polymorphous nuclei with a Ki-67 labeling index of 10% consistent with parathyroid carcinoma. Post-surgery imaging with ultrasound and magnetic resonance imaging of the neck computed tomography of the chest, and abdomen, whole-body MIBI scintigraphy was negative for residuals or metastatic disease. She was started on oral calcium carbonate and was monitored regularly with routine lab work. The most recent lab work was within normal limits. Conclusion: Most of the patients with parathyroid carcinoma present in the early stage with the symptoms of hypercalcemia. Many of them do not have symptoms of mass or tumor effects. Parathyroid cancer is a rare malignancy and can be missed, therefore all patients with hypercalcemia should be further evaluated with lab work, imaging, and biopsy to rule out parathyroid carcinoma. Early diagnosis and treatment have a better outcome.

Genetic Testing in a Patient With Suspected Hyperparathyroidism- Jaw Tumor Syndrome (HPT-JT)

Abstract Introduction: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disorder characterized by parathyroid tumors in association with fibro-osseous jaw tumors, uterine tumors and renal lesions. We present a case of suspected HPT-JT. Clinical Case: A 50-year-old female with suspected HPT-JT was referred for treatment of osteoporosis. Patient was initially diagnosed with osteosarcoma in 1980 at age 10, and underwent resection with leg amputation and chemotherapy. Around 1995, she was found to have primary hyperparathyroidism secondary to a parathyroid adenoma and underwent one gland parathyroidectomy. At age 30, she was then found to have multiple uterine tumors requiring hysterectomy. In 2017, she underwent CT abdomen for suspected appendicitis, which revealed multiple renal cysts and hepatic hemangiomas. In 2019, patient was found to have recurrent parathyroid adenoma and underwent revision parathyroidectomy. Pathology revealed hypercellular parathyroid gland consistent with adenoma. Based on constellation of symptoms, HPT-JS was suspected. Patient was referred to genetic counselor. Detailed family history revealed multiple family members affected by malignancies including melanoma, breast cancer, prostate cancer, liver cancer and two cousins with suspected MEN1. She underwent testing for hereditary hyperparathyroidism and melanoma including CDC73 gene. All genetic testing was surprisingly unrevealing. Discussion: CDC73 gene (also known as HRPT2 gene) is responsible for the pathogenesis of HPT-JT. While HPT-JT itself is a rare condition, 60% of patients affected by it, harbor the HRPT2 gene mutation. About 10–15% of these individuals are affected by parathyroid carcinoma. HRPT2 mutated parathyroid adenomas also seem to have some malignant potential. The autosomal dominant inheritance of HPT-JT makes gene testing important since it has implications for other family members and carries weight in clinical management of genetic carriers. Therefore patients with extensive personal or family history of malignancy should be followed closely. Endocrinologists should have a low threshold to refer such patients for genetic counseling and testing. However genetic testing also has its limitations and can only explain 50–75% of cases of HPT-JT syndrome. Hence, even though our patient has a negative genetic screen, the possibility of HPT-JT is not complete ruled out.

A case report of a patient with parathyroid carcinoma and a CDC73 germline mutation

Background: Parathyroid carcinoma (PC) is an uncommon cause of primary hyperparathyroidism (pHPT). Mutations of the cell division cycle protein 73 homolog (CDC73) gene are associated with both sporadic and familial pHPT and PC, including hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Case Presentation: A 38-year-old man presented with severe hypercalcemia and acute renal injury due to pHPT. He had a palpable left cervical mass of 50 mm, characterized by both ultrasound and 99mTc-sestamibi scintigraphy as an enlarged hyperfunctioning parathyroid gland. Histological diagnosis after parathyroidectomy was of PC. During follow-up, patient developed metastasis of the skin, mediastinal lymph-nodes, and lungs. Even after surgical excision of all detectable metastasis parathyroid hormone (PTH) remained elevated. Genetic analysis found a germline mutation (c.766_767delGT) of the CDC73 gene, which was not previously reported in PC. Conclusion: Germline CDC73 analysis may be considered in HPT-JT syndrome, familial isolated pHPT, PC, and young individuals with pHPT.

Remission of disseminated parathyroid cancer after multiple surgical interventions because of recurrences in the neck lymph nodes, left lung and liver in a young patient with hyperparathyroidism-jaw tumor syndrome

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

Secondary renal neoplasia following chemotherapy or radiation in pediatric patients

Renal neoplasia occurring as a second malignancy following childhood cancer has been most closely associated with neuroblastoma and Wilms tumor. While some cases have been associated with a genetic predisposition, nearly all are thought to result from "late effects" of therapy-related toxicity that involves chemotherapy or radiation. It is unclear if these tumors are enriched for specific molecular or morphologic characteristics. A query of our institutional nephrectomy registry of 8295 patients for renal neoplasia occurring post-treatment for childhood cancer revealed 6 patients with Wilms tumor, 4 with neuroblastoma, and 1 with acute lymphoblastic leukemia (ALL). Three additional cases of MiT family translocation renal cell carcinoma (RCC), from 2 patients, following chemotherapy for neuroblastoma and systemic lupus erythematosus and another of clear cell RCC post-ALL were included. The most common tumor type was clear cell RCC: 9/19 cases (47.4%), followed by metanephric adenoma and MiT family translocation RCC (3/19, 15.8%). There were no characteristic features to indicate a unique renal neoplasia subtype. Potential syndromic renal neoplasia occurred in 2 patients, metanephric adenomas and oncocytoma in a patient with hyperparathyroidism-jaw tumor syndrome post-treatment of Wilms tumor and a fumarate hydratase-deficient RCC in a patient post-treatment for ALL. The mean age at diagnosis of childhood neoplasia or treatment with chemotherapy or radiation was 4.7 years, and the average time to subsequent renal neoplasia was 31 years. Five (of 14) patients developed metastatic RCC, and there were 2 RCC-related deaths. These results indicate the need for extended clinical follow-up of these patients.

Gnathic Bones and Hyperparathyroidism: A Review on the Metabolic Bony Changes Affecting the Mandible and Maxilla in case of Hyperparathyroidism.

Parathyroid glands secrete the parathyroid hormone that plays an essential role in bone remodeling. Excessive production of parathyroid hormone causes a common metabolic bone disorder known as hyperparathyroidism that is classified into primary, secondary, or tertiary. In hyperparathyroidism, the late bony complication is manifested as a giant cell osteolytic lesion called “brown tumor.” Primary hyperparathyroidism is usually a sporadic disorder, but in minority of cases it occurs in inherited forms, and one of these forms is the hyperparathyroidism-jaw tumor syndrome, which is characterized by primary hyperparathyroidism and ossifying fibroma in the mandible and/or maxilla.