Lipoadenoma of the parathyroid: characteristics of a rare cause of hyperparathyroidism.

Parathyroid Lipoadenoma (PLA) contains abundant mature adipose tissue and is a rare cause of hyperparathyroidism. This study aimed to investigate the clinical features of PLA in nine patients with primary hyperparathyroidism, including two men and seven women, with ages ranging from 45-84 years (median 60 years). PLA accounted for 0.5% of all parathyroid tumors during the study period. One patient presented with anorexia due to hypercalcemia; however, the other eight patients were asymptomatic. The median preoperative serum intact-parathyroid hormone (iPTH) and calcium levels were 143 pg/mL (range, 102-378) and 10.8 mg/dL (range, 10.3-11.3), respectively. PLA was difficult to identify using ultrasonography (US) as it appears as a moderately hyperechoic nodule and is difficult to distinguish from the surrounding adipose tissues. Only 33% of the lesions (three out of nine lesions) were accurately identified. However, they could be distinctly differentiated from the surrounding tissue using computed tomography (CT). All PLAs were also detected using the sesta-methoxyisobutylisonitrile single-photon emission-computed tomography (SPECT). All the patients were treated by a single gland extirpation. The median size and weight of the PLA were 14 mm (range, 10-22) and 567 mg (range, 200-1,533), respectively. In conclusion, the clinical manifestations of PLA are similar to those of ordinal parathyroid adenomas, except for their unique US and CT images. PLA should be considered as a potential etiologic factor in cases of hyperparathyroidism when the lesions are demonstrated as hyperechoic nodules or unidentified by US but detected by CT or SPECT imaging.

Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone-Secretory Tissue.

Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in CASR, GNA11, or AP2S1. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the CASR. 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of MEN1 or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from RET activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in CDC73. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT-JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects GCM2 activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression.

[CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases]. / Mutatsii v gene CDC73 u molodykh patsientok s pervichnym giperparatireozom (opisanie dvukh klinicheskikh sluchaev).

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

Brown tumor of hyperparathyroidism involving craniomaxillofacial region: a rare case report and literature review.

Central giant cell granuloma (CGCG) is a benign, non-odontogenic bone lesion of jaw. The condition is relatively infrequent and affects mainly children and young adults with a certain predominance among females and exhibits variable aggressiveness. Giant cell lesion associated with hyperparathyroidism is known as Brown tumor. Brown tumor is one of the bony complications of hyperparathyroidism. It is a giant cell granuloma which occurs in osteitis fibrosis cystica. It represents the terminal stage of the bone remodelling processes occurring as a result of peritrabecular fibrosis and osteoclastic activity. The mandible is the predominantly affected site in the maxillofacial area. Maxillary involvement is rare. The incidence of Brown tumor associated with hyperparathyroidism is rare (0.1%). Here, an extremely rare case of a 20 year old female patient with Brown tumor in her maxilla and mandible associated with primary hyperparathyroidism was presented. A thorough diagnostic work up showed presence of tumor mass in mandible and maxilla and elevated serum alkaline phosphatase and parathormone level and the patient was treated for both hyperparathyroidism and Brown tumor were discussed. The importance of different radiological evaluation methods and the consultation between the oral and maxillofacial surgeons, dentists, endocrinologists and radiologists were emphasized.

Hereditary Parathyroid Disease: Sometimes Pathologists Do Not Know What They Are Missing.

Parathyroid gland excision specimens are common and sometimes underestimated cases that many surgical pathologists encounter regularly. In the vast majority of cases, these will be spot diagnoses of sporadic primary parathyroid adenomas or, perhaps, hyperplasias commonly in the setting of renal failure. However, a small but significant number of parathyroid gland excisions may be due to heritable disease. In most cases, hereditary disease is suspected by the referring clinicians. Nevertheless, a subset of these are undetected which is significant, particularly in the setting of the multiple endocrine neoplasia (MEN), and the hyperparathyroidism jaw tumour (HPT-JT) syndromes. There have been recent advances in recognition of the morphological and immunohistochemical characteristics of these tumours and hyperplasias. While hereditary kindreds are over-represented at specialist referral centres, with awareness of the characteristic clinical and morphological features, the general surgical pathologist is frequently able to suggest the possibility of hereditary parathyroid disease. We therefore provide a succinct guide for pathologists to increase the recognition of hereditary parathyroid disease.

Photodynamic diagnosis of parathyroid glands with nano-stealth aminolevulinic acid liposomes.

Background The use of ALA to identify the parathyroid glands had been investigated both experimentally and clinically with promising results but the side effects from the systemic use of this photosensitizer reduce its widespread in clinical use. The aim of this study is to test the formulation of ALA in nano-stealth liposomes for better photodiagnosis of parathyroid glands intraoperatively with less ALA dose. MATERIALS AND METHODS: Preparation of ALA nanovesicles and in vitro characterization for the drug encapsulation percentage, vesicle size and Zeta potential then the study of nanovesicles stability and in vitro drug release profile was done. The study compared nano-stealth liposomes and nano-liposomes with the free ALA solution, intraperitoneal administration of these different ALA formulations in rats and observing the ability to identify parathyroids intraoperatively and evaluation of fluorescence differences between these groups. RESULTS AND CONCLUSION: Stealth liposomes were insignificantly higher in drug encapsulation%, in vitro drug release and zeta potential compared to conventional liposomes. Additionally, they needed less time for the start of the photosensitization and recorded the highest signal after spectrometry compared to the other two preparations. These data provide a new evidence of the potentiality of ALA-stealth Liposomes for identification of PTGs intraoperatively and could lead to propose a non-invasive procedure with reduced postoperative side effects.

Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias.

Parathyroid carcinoma is notoriously difficult to diagnose with confidence in borderline cases. Commonly there is a long lag time between diagnosis and clinical evidence of malignant behavior even in histopathologically straightforward lesions. There is therefore a need for a novel adjunctive marker to assist in the diagnosis of carcinoma. Parafibromin is the protein encoded by the putative tumor suppressor gene HRPT2. Mutations predicted to inactivate parafibromin were first detected in the germline of patients with hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Subsequently, somatic mutations have been identified in the majority of sporadic carcinomas. We performed immunohistochemistry for parafibromin on 115 parathyroid tissues comprising 4 HPT-JT-related tumors (3 adenomas and 1 carcinoma), 11 sporadic parathyroid carcinomas, 79 sporadic adenomas, 3 multiple endocrine neoplasia 2A-related adenomas, 2 sporadic primary hyperplasias, 2 multiple endocrine neoplasia (MEN)-1-related hyperplasias, 6 secondary hyperplasias, 4 tertiary hyperplasias, and 4 normal parathyroid glands. There was complete absence of nuclear staining in 3 of 4 (75%) HPT-JT-related tumors and 8 of 11 (73%) sporadic parathyroid carcinomas and focal weak staining in 1 of 4 HPT-JT tumors and 2 of 11 sporadic parathyroid carcinomas. Only 1 parathyroid carcinoma exhibited diffuse strong nuclear expression of parafibromin. In contrast, 98 of 100 non-HPT-JT-related benign parathyroids showed diffuse strong nuclear positivity and 2 of 100 showed weak positive staining. We conclude that, in the correct clinical and pathologic context, complete absence of nuclear staining for parafibromin is diagnostic of parathyroid carcinoma or an HPT-JT-related tumor.

[Prophylactic parathyroidectomy for familial parathyroid carcinoma]. / Das familiäre Nebenschilddrüsenkarzinom Indikation zur prophylaktischen Parathyreoidektomie?

In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

From mild to severe primary hyperparathyroidism: The Brazilian experience.

Primary hyperparathyroidism often presents as an asymptomatic disorder. In our institution, routine serum calcium measurements have now been used as part of medical examination for 23 years. Out of 124 patients consecutively seen at our institution, 47% presented with no symptoms related to the disease, while 25% presented with severe skeletal involvement and osteitis fibrosa cystica, 25% with renal stone disease without overt bone involvement, and 2% with the typical neuropsychiatric syndrome. This same pattern is seen in the city of São Paulo. In severe disease pathological fractures are frequently seen, especially in long bones of the lower extremities, and also loss of lamina dura of the teeth and salt-and-pepper appearance of the skull. Bone mineral density is extremely low in these patients but usually show remarkable recovery following surgical cure. Serum PTH and bone markers are considerable higher in severely affected patients, who also have a high rate of vitamin D deficiency, and the parathyroid lesion is easier located compared with asymptomatic patients. From pathological specimens 87% had histological confirmation of a single adenoma, 6.4% multiple gland hyperplasia and 3.8% carcinoma.

Giant cell tumours of the maxilla and tibia presenting concurrently as an initial manifestation of primary parathyroid adenoma.

A 14 years female of Afghan origin reported with maxillofacial and tibia growths causing progressive deformities since nine months, both were giant cell tumours on histopathology. Serum calcium was normal, but the parathyroid hormone was exaggerated (678 pg/ml). Ultrasound indicated and Tc-99m Setamibi scan confirmed a left lower parathyroid lesion. A 4cm length mass was identified, removed and proved to be a parathyroid adenoma. Two weeks later a subtotal maxillectomy and six weeks later anterior wedge osteotomy of the tibia were carried out. Serum parathyroid hormone level normalized.

Clinicopathological correlates of hyperparathyroidism.

Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3ß, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/ß-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80-85%), hyperplasia (10-15%) and carcinoma (<1-5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of families.

Approximately 70 families with familial isolated hyperparathyroidism (FIHP) have been reported. Whether it is a separate entity or a variant of multiple endocrine neoplasia type 1 (MEN1 at 11q13) or hyperparathyroidism-jaw tumor (HPT-JT or HRPT2 at 1q21-32) syndrome is not known. We describe here 3 unreported families with familial primary hyperparathyroidism and evaluate their clinical, pathological, and genetic profiles. Biochemical and radiological screenings for MEN1 were negative for all families. In 2 families with a total of 10 affected cases and 3 female obligate carriers, there is no evidence of jaw or renal lesions despite careful radiological investigations. In both families the disease was linked to the 1q21-q32 region with the maximum logarithm of the odds (lod) scores of 3.10 and 3.43 for markers D1S222 and D1S249 respectively, at recombination fraction of 0. In 1 family 2 types of parathyroid pathology were found: 3 of chief cell type and 1 of oxyphil/oncocytic cell type. Two chief cell tumors and 1 oxyphil tumor were found to have loss of heterozygosity (LOH) involving loss of the wild-type alleles for chromosome 1q markers. In the third family, with 4 affected siblings, a parathyroid carcinoma and 2 cases of polycystic kidney disease were found. The parathyroid carcinoma also showed loss of heterozygosity in the 1q region. In conclusion, we found that the hyperparathyroidism traits in a subset of FIHP families are linked to the 1q21-32 markers in the HRPT2 region. We describe the spectrum of parathyroid disease in 1q-linked families involving 3 different types of pathology and demonstrate for the first time loss of wild-type alleles in these parathyroid tumors. Taken together, the results suggest that some of the FIHP are a variant of HPT-JT and that the gene involved is a tumor suppressor gene.

Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.

Familial isolated hyperparathyroidism (FIHP) can result occasionally from the incomplete expression of a syndromic form of familial hyperparathyroidism (HPT), specifically multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric hypercalcemia, or the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The cause of FIHP has not been identified in the majority of families. We investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT. All families had negative clinical testing for MEN1, hypocalciuric hypercalcemia, and HPT-JT and negative mutational screening of MEN1 and CASR, the gene for the calcium-sensing receptor. Thus, an extended effort was made to exclude each of the principal syndromic causes of FIHP. The families were characterized by young probands (42 +/- 3 yr) and occasionally unusual parathyroid histology, including four families with one case of parathyroid cancer. We had speculated that there was a high frequency of occult mutation in HRPT2 among such carefully screened kindreds. This hypothesis became testable with the recent identification of that gene. Among the 32 FIHP families, only a single one was found to have a mutation in HRPT2 (679insAG); this mutation predicts premature truncation of its gene product, parafibromin, and thus its presumed inactivation. Even accounting for families with one of the three occult syndromes and false negative biochemical or DNA testing, these results indicate that an unexpectedly large fraction of FIHP has currently unrecognized causes.

[Effect of the hypothyroidism-castration association on bone and parathyroids from adult female rats]. / Efeito da associação hipotireoidismo-castração no osso e nas paratireóides de ratas adultas.

The effect of hypothyroidism on bone metabolism and the parathyroids in states of deficiency or sufficiency of sex steroids was studied in 32 two-months-old female Wistar rats distributed in 4 groups of 8 animals each: intact euthyroid (IE), castrated euthyroid (CE), intact hypothyroid (IH) and castrated hypothyroid (CH). After 120 days of treatment, animals were sacrificed and plasma taken to assess free T4. Hyperplasia or hypertrophy of all parathyroids were evident only in IH and CE groups. Of all groups, IH rats presented the most extensive osteopenia, reaching lumbar vertebrae, dental alveolae (jaw and mandible) and long bones. In this group osteopenia resulted from the reduced bone growth, inhibition of bone apposition and return of bone resorption. Although osteopenia in the CH group was almost always more intense in relation to osteopenia presented by CE rats, its intensity was variable when compared to IH rats and dependent on the region studied. Even though it also caused necrosis of higher metabolism bones, the association hypothyroidism-castration did not potentialize the resultant osteopenia of the isolated action of hypothyroidism or castration until 120 days of treatment.

An exceedingly rare localization of a brown tumor in a hemodialysis patient.

Brown tumor, which is seen in the context of hyperparathyroidism, is defined as a uremic bone disease characterized by increased osteoclastic activity and fibroblastic proliferation in the involved bone. In chronic renal failure, there is an excessive parathyroid hormone secretion due to hypocalcemia, hyperphosphatemia, and vitamin D deficiency. Brown tumor of the femur, facial bones, mandible, sternum, ribs, and pelvis are rare, whereas, it rarely involves sacrum. Here, we presented a brown tumor of the sacrum that developed secondary to parathyroid hyperplasia in a patient receiving hemodialysis.

The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome.

Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation.

Parathyroid pathology: hyperparathyroidism and parathyroid tumors.

CONTEXT: Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Parathyroid adenomas are common, unlike other parathyroid tumors. This review presents a brief summary of current updates in parathyroid pathology. OBJECTIVE: To review parathyroid development and discuss issues in hyperparathyroidism and diagnosis of parathyroid lesions, including the application of immunohistochemistry and molecular biology. DATA SOURCES: Current texts, PubMed (National Library of Medicine) articles, and Memorial Sloan-Kettering Cancer Center archives. CONCLUSIONS: Primary hyperparathyroidism is most commonly seen with sporadic adenomas, followed by hyperplasia, multiple adenomas, and carcinoma. Autosomal dominant familial hyperparathyroidism syndromes should be considered in the evaluation of patients with parathyroid lesions, particularly in association with parathyroid carcinoma. While the incidence of parathyroid carcinoma is quite low, it is seen with a greater frequency in those patients with hyperparathyroidism-jaw tumor syndrome. Inactivation of the tumor suppressor gene HRPT2 can be identified in a large number of parathyroid carcinomas. Hence, germline HRPT2 gene mutations may reflect unrecognized syndromic patients.

"An exophytic mandibular brown tumor": an unusual presentation of primary hyperparathyroidism.

CASE REPORT: A case of 35-year-old male patient with previously undiagnosed primary hyperparathyroidism who presented with an atypical exophytic mandibular swelling is reported. PURPOSE: The aim is to alert the clinicians to include this entity although extremely rare, in the differential diagnosis of swellings in the maxillofacial region and to highlight another remarkable aspect in the multitude of presentations associated with primary hyperparathyroidism especially in the setting of normocalcemia.

[Primary hyperparathyroidism in an adolescent. Report of one case]. / Hiperparatiroidismo primario en el adolescente: Caso clínico.

We report a 13 year-old mate with a history of multiple fractures and kidney stones. The laboratory showed a hypercalcemia of 11.5 mg/dl, a PTH of 112.6 pg/ml and 24 hour urinary calcium of 571 mg. Bone densitometry showed spine and femur Z scores of -2.9 and -1.6, respectively, kidney ultrasound showed nephrocalcinosis and a MIBI-SPECT scintigram showed a higher uptake in the right lower parathyroid gland. The diagnosis of primary hyperparathyroidism was made and the patient was operated, excising the right lower parathyroid gland. After surgery, serum calcium and PTH levels returned to normal values. In children, the proportion of cases with parathyroid hyperplasia is higher than in adults. Therefore, during surgery all four parathyroid glands must be explored. There is also a higher frequency of ectopic adenomas. Family history must be explored to discard the presence of a multiple endocrine neoplasia (MEN I or II), a familial hyperparathyroidism or a syndrome of primary hyperparathyroidism associated to mandibular tumor.