Multiglandular Parathyroid Research Articles

Dual-tracer subtraction scintigraphy combined with SPECT/CT in preoperative patients with primary hyperparathyroidism.

Abstract.

Primary Multiglandular Parathyroid Disease in the Setting of Pompe Disease.

Primary Multiglandular Parathyroid Disease in the Setting of Pompe Disease.

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

Predicting the presence of MEN1 gene mutation based on the clinical phenotype of patients with primary hyperparathyroidism

Timely referral of patients for genetic testing to rule out MEN1-associated primary PHPT is important factor in determining treatment strategy and prognosis. In the context of the limited availability of genetic testing, the search for clinical markers indicative of MEN1 gene mutations remains an extremely relevant task. To determine the diagnostic value of clinical features of primary PHPT in young patients for predicting the presence of MEN1 gene mutations. A single-center, prospective study was conducted at the Endocrinology Research Centre, involving 273 patients with PHPT in the period 2015-2022. Based on the results of genetic and laboratory tests, patients were divided into three groups: those with MEN1 gene mutations (MEN+ group, n=71), those without MEN1 gene mutations - isolated sporadic PHPT (MEN- group, n=158), and patients with PHPT and associated endocrine gland disorders - MEN-1 syndrome phenocopies (PHEN group, n=32). Subgroups of patients younger than 40 years of age were also identified. Comparative analysis was performed among the independent groups and subgroups, and logistic regression analysis was used to develop a mathematical model for predicting the probability of the presence of MEN1 gene mutation. Patients in the MEN+ and MEN- groups were comparable by gender and age at manifestation, as well as calcium-phosphorus metabolism parameters and PHPT complications. In the PHEN group, PHPT manifested at older age compared to the other groups (p<0.001 for all), with lower total calcium levels and a trend toward lower iPTH concentrations. The MEN+ group had a significantly higher frequency of multiglandular parathyroid (PG) involvement, PHPT recurrence, and positive family history compared to the MEN- and PHEN groups. Histologically, adenomas predominated in the PHEN and MEN- groups (92% and 94%, respectively), whereas hyperplasia of PGs were more common in the MEN+ group (49%). None of the PHEN patients had all three «classic» components of the MEN-1 syndrome, and the clinical course of PHPT was similar to that of the MEN- group. These differences were also observed in the subgroups of patients younger than 40 years, which formed the basis for the development of a mathematical model. The logistic regression equation for predicting the probability of the presence of the MEN1 gene mutation included eight predictors, with a diagnostic sensitivity of 96% and specificity of 98%. Based on the analysis performed, eight hereditary predictors of PHPT within the MEN-1 syndrome were identified. A mathematical model was developed to predict the presence of the MEN1 gene mutation in patients, which demonstrated high classification performance on the training dataset. Further refinement of the model will help improve the quality of medical care for patients with PHPT.

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

Bilateral giant parathyroid adenoma and hungry bone syndrome: a case report

BackgroundThere is some evidence supporting the idea that double parathyroid adenomas represent a different entity from multiglandular hyperplasia; however, the distinction among them is not straightforward.Case presentationWe described a case of primary hyperparathyroidism (PHPT) with pronounced clinical manifestations, caused by a bilateral giant parathyroid adenoma. A 34-year-old Hispanic/Latino male was diagnosed with PHPT caused by two giant parathyroid adenomas. The preoperative tests were neck ultrasound and computed tomography scan (CT-scan), showing two masses in the territory of parathyroid glands, bilaterally distributed (right was 31 × 18 × 19 mm and the left was 38 × 15 × 14 mm); sestamibi scan was not available. Parathyroid hormone (PTH) was highly elevated. Multiple complications of PHPT were present, such as bone lytic lesions, renal and pancreatic calcifications, and cardiovascular disease, the latter of which is an overlooked complication of PHPT. Multiple endocrine neoplasia 1 and 2 (MEN 1/2) were ruled out by the absence of clinical, biochemical, and radiological findings in other endocrine glands. The patient underwent subtotal parathyroidectomy with an intraoperative histopathological study; both intraoperative and definitive histopathology results were consistent with parathyroid adenomas; afterward, adequate suppression of PTH was assured, and later on, the patient presented hungry bone syndrome (HBS).ConclusionsThe diagnosis of double parathyroid adenomas is difficult. Regarding the similarities between multiglandular hyperplasia and parathyroid adenomas, this case report contributes to the further distinction between these two clinical entities. This case report also represents, in particular, the challenge of difficult diagnosis in places with limited resources, such as developing countries.

Advances and Updates in Parathyroid Pathology.

Hyperparathyroidism is a common endocrine disorder characterized by elevated levels of parathyroid hormone and hypercalcemia and is divided into 3 types: primary, secondary, and tertiary. Distinction between these types is accomplished by correlation of clinical, radiologic, and laboratory findings with pathologic features. Primary hyperparathyroidism occurs sporadically in 85% of cases with the remaining cases associated with multiple familial syndromes. The pathologic manifestations of primary hyperparathyroidism include parathyroid adenoma, parathyroid hyperplasia, and parathyroid carcinoma. Recent advances in the understanding of the pathogenesis of parathyroid disease has helped to refine the diagnosis and classification of parathyroid lesions. The identification of multiple clonal proliferations in traditional multiglandular parathyroid hyperplasia has led to the adoption by the World Health Organization (WHO) of the alternate term of primary hyperparathyroidism-related multiglandular parathyroid disease. Additional nomenclature changes include the adoption of the term atypical parathyroid tumor in lieu of atypical parathyroid adenoma to reflect the uncertain malignant potential of these neoplasms. Clinical and morphologic features characteristic of familial disease have been described that can help the practicing pathologist identify underlying familial disease and provide appropriate management. Use of ancillary immunohistochemistry and molecular studies can be helpful in classifying parathyroid neoplasms. Parafibromin has proven useful as a diagnostic and prognostic marker in atypical parathyroid tumors and parathyroid carcinomas. This review provides an update on the diagnosis and classification of parathyroid lesions considering the recent advances in the understanding of the molecular and clinical features of parathyroid disease and highlights the use of ancillary studies (immunohistochemical, and molecular) to refine the diagnosis of parathyroid lesions.

PSUN76 Massive Four-Gland Parathyroid Hyperplasia: The Case of the Missing Glands

Abstract Introduction Parathyroid adenoma (PA) and parathyroid hyperplasia (PH) are common causes of primary hyperparathyroidism (PHPT) for which the only definitive treatment is surgical removal. Surgery is often preceded by imaging for localization, including by ultrasound (US), Sestamibi scan (MIBI), positron emission tomography/computer tomography (PET/CT), and four-dimensional computed tomography (4D-CT). While it is common for parathyroid pathology to not be visualized on imaging, non-visualization is more typical of adenomas and hyperplasia of smaller size. Clinical Case A 65-year-old male without history of kidney dysfunction or family history of parathyroid disease was referred to surgery for parathyroidectomy to manage longstanding PHPT. Serology showed a parathyroid hormone (PTH) level of 581 pg/mL (reference range: 12-65 pg/mL) and calcium of 11.8 mg/dL (reference range: 8.6-10.5 mg/dL). Preoperative parathyroid localization US revealed a large well-defined 1.5 cm PA. The patient underwent parathyroidectomy, which detected a large right inferior parathyroid gland, confirmed with pathology to be an atypical parathyroid adenoma weighing 1800 mg. Postoperative PTH level was 550 pg/mL and calcium was 12.6 mg/dL. MIBI did not display any definite parathyroid adenoma or ectopic parathyroid tissue. Further evaluation with PET/CT did not demonstrate any evidence of metabolically active residual or ectopic parathyroid adenoma or metastatic disease, and repeat US showed did not reveal evidence of any abnormal parathyroid tissue. Ultimately, 4D-CT detected a multiglandular parathyroid with a 1.8×1.4×3.0 cm right superior adenoma weighing approximately 3931 mg, 1.2×0.8×2.1cm left superior adenoma weighing approximately 1048 mg, and a 0.3×0.4×0.4cm left superior adenoma weighing approximately 25 mg. The patient underwent re-exploration parathyroidectomy with removal of the right superior adenoma weighing 3105 mg and left superior adenoma weighing 1100 mg. The remaining left inferior gland was biopsied and the majority of it was implanted into the arm. Repeat serology one week post-operatively showed improvement of PTH level to 5 pg/mL and of calcium to 8.9 mg/dL and serology one year post-operatively showed a PTH level of 82 pg/mL and a calcium of 9.4 mg/dL. Conclusion We present a patient with massive four-gland PH who initially presented with findings more typical of PA, but ultimately had additional hyperplasic glands that were identified after removal of the adenomatous gland. These glands were unusually large to be seen in PH and yet still be undetected on multiple imaging modalities; no previously reported non-ectopic hyperplastic glands of this size have been documented that were not detected on US or MIBI. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Multiglandular Parathyroid Disease.

Introduction: Multiglandular parathyroid disease (MGD) is an uncommon cause of primary hyperparathyroidism (pHPT) and has been reported in the literature in 8–33% of patients with pHPT. The aim of our study was to review the clinical characteristics and management of MGD and evaluation of surgical treatment failures. Methods: We performed a retrospective study of 163 patients with pHPT undergoing parathyroidectomy (PTX) at the Department of General and Endocrine Surgery between 1983 and 2018. All these patients were diagnosed with MGD. This group of patients was compared with a group of 856 patients with solitary disease operated for pHPT in the same period. Results: Among 163 patients—127 (79%) of them had two lesions, 28 (16%) had three, and 8 (5%) four. They were prevalently women over the age of 50. The diagnosis was based on PTH and ionized calcium studies and used sestamibi technetium-99m scintigraphy (MIBI) as well for us. Treatment was surgical. Conclusions: Parathyroidectomy (PTX) for multiglandular parathyroid disease (MGD) is associated with a higher operative risk of failure compared to solitary disease. Preoperative diagnosis and localization of the parathyroid glands is an extremely important element of treatment. Diagnosis is based on PTH and calcium levels. Ultrasonography (USG), MRI, and scintigraphy are very helpful in diagnosis. Mediastinal multiglandular parathyroid disease (MGD) is associated with increased surgical treatment failures. The treatment is surgical and consists of the removal of the masses or complete parathyroidectomy. Based on this study, we support the existence of multiple adenomas and advocate the removal of only macroscopically enlarged parathyroid glands in patients with primary hyperparathyroidism.

Multiglandular Parathyroid Disease in Primary Hyperparathyroidism With Inconclusive Conventional Imaging.

Inconclusive preoperative imaging is a strong predictor of multiglandular parathyroid disease (MGD) in patients with primary hyperparathyroidism (PHPT). MGD was investigated in a cohort of 17 patients with PHPT (mean age 64.9 years, total calcium 2.75 mmol/l and parathyroid hormone (PTH) 113.3 ng/l) who underwent 18F-fluorocholine PET/CT (FCH) imaging before surgery. The initial MIBI SPECT scintigraphy (MIBI) and/or neck ultrasound were not conclusive or did not localize all pathological parathyroid glands, and PHPT persisted after surgery. Sporadic MGD was present in 4 of 17 patients with PHPT (24 %). In 3 of 4 patients with MGD, FCH correctly localized 6 pathological parathyroid glands and surgery was successful. Excised parathyroid glands were smaller (p <0.02) and often hyperplastic in MGD than in single gland disease. In two individuals with MGD, excision of a hyperplastic parathyroid gland led to a false positive decline in intraoperative PTH and/or postoperative serum calcium. Although in one patient it was associated with partial false negativity, parathyroid imaging with FCH seemed to be superior to neck ultrasound and/or MIBI scintigraphy in MGD.

Overview of the 2022 WHO Classification of Parathyroid Tumors.

The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features of parathyroid neoplasms, subtleties in histologic features which may indicate an underlying genetic abnormality reflect increased understanding of the clinical manifestations, histologic, and genetic correlation in parathyroid disease. The importance of underlying genetic aberrancies is emphasized due to their significance to the care of the patient. Traditionally, the term "parathyroid hyperplasia" has been applied to multiglandular parathyroid disease; however, the concept of hyperplasia is generally no longer supported in the context of primary hyperparathyroidism since affected glands are usually composed of multiple "clonal" neoplastic proliferations. In light of these findings and management implications for patient care, the 2022 WHO classification endorses primary hyperparathyroidism-related multiglandular parathyroid disease (multiglandular multiple parathyroid adenomas) as a germline susceptibility-driven multiglandular parathyroid neoplasia. From such a perspective, pathologists can provide additional value to genetic triaging by recognizing morphological and immunohistochemical harbingers of MEN1, CDKN1B, MAX, and CDC73-related manifestations. In the current WHO classification, the term "parathyroid hyperplasia" is now used primarily in the setting of secondary hyperplasia which is most often caused by chronic renal failure. In addition to expansion in the histological features, including those that may be suggestive of an underlying genetic abnormality, there are additional nomenclature changes in the 2022 WHO classification reflecting increased understanding of the underlying pathogenesis of parathyroid disease. The new classification no longer endorses the use of "atypical parathyroid adenoma". This entity is now being replaced with the term of "atypical parathyroid tumor" to reflect a parathyroid neoplasm of uncertain malignant potential. The differential diagnoses of atypical parathyroid tumor are discussed along with the details of worrisome clinical and laboratory findings, and also features that define atypical histological and immunohistochemical findings to qualify for this diagnosis. The histological definition of parathyroid carcinoma still requires one of the following findings: (i) angioinvasion (vascular invasion) characterized by tumor invading through a vessel wall and associated thrombus, or intravascular tumor cells admixed with thrombus, (ii) lymphatic invasion, (iii) perineural (intraneural) invasion, (iv) local malignant invasion into adjacent anatomic structures, or (v) histologically/cytologically documented metastatic disease. In parathyroid carcinomas, the documentation of mitotic activity (e.g., mitoses per 10mm2) and Ki67 labeling index is recommended. Furthermore, the importance of complete submission of parathyroidectomy specimens for microscopic examination, and the crucial role of multiple levels along with ancillary biomarkers have expanded the diagnostic workup of atypical parathyroid tumors and parathyroid carcinoma to ensure accurate characterization of parathyroid neoplasms. The concept of parafibromin deficiency has been expanded upon and term "parafibromin deficient parathyroid neoplasm" is applied to a parathyroid neoplasm showing complete absence of nuclear parafibromin immunoreactivity. Nucleolar loss is considered as abnormal finding that requires further molecular testing to confirm its biological significance. The 2022 WHO classification emphasizes the role of molecular immunohistochemistry in parathyroid disease. By adopting a question-answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the underlying pathogenesis of parathyroid disease that are now reflected in the updated classification and new entities in the 2022 WHO classification.

Consideration of primary hyperparathyroidism in primary care

A sixty-seven-year-old female patient presented with symptomatic hypercalcemia as the first manifestation of primary hyperparathyroidism due to parathyroid adenoma. Initially the chronic hypercalcemia was investigated and then subsequent parathyroidectomy was done. She is doing very well six months following the surgery and the hypercalcemia has resolved completely. Asymptomatic hypercalcaemia due to primary hyperparathyroidism is a common condition in primary care1. Most commonly primary hyperparathyroidism is caused by a solitary parathyroid adenoma (80%), and less frequently multi-glandular adenoma, parathyroid hyperplasia or carcinoma2. Patients rarely present with symptomatic hypercalcemia (mnemonic “stones,” “bones,” “abdominal moans,” and “psychic groans”) whereas usually patients remain asymptomatic and the condition is discovered during routine checkup investigations3. The disorder can occur at any age, yet is more common in the middle age group (≥50 years). The ratio of such cases is equivalent to 1:1000 in males, whereas it is 3:1000 in the female population4.

An Unusual Presentation of Primary Hyperparathyroidism: Ectopic Parathyroid Gland and Multiglandular Disease

Primary hyperparathyroidism (PHPT) can be associated as a single parathyroid adenoma in approximately 85% of patients, the remaining 15% of them correspond to individuals with hyperplasia. The multiglandular parathyroid disease varies in range 7–33% and contribute a persistent PHPT. We report a case of primary hyperparathyroidism with an unusual presentation of ectopic mediastinal parathyroid. The case was of a 54-year-old female, who started her illness 3 years ago, with frequent headache, regular fatigue and muscle pain, denied losing weight. She was admitted to emergency room for a urinary infection. During the hospitalization showed bilateral nephrocalcinosis, hypercalcemic crisis. She has a background of total thyroidectomy and subtotal parathyroidectomy because a thyroid adenomatous hyperplasia and parathyroid hyperplasia with removal of a total of three parathyroid glands. She had very high PTH level. Laboratory: serum calcium: 16.8mg/dl; ionic calcium: 2.37 mmol/L; P: 1.9 (2.7–4.5g/dL); Hb: 9 g/dL; Platelets: 558 000 per microliter; Leukocytes 9 600 cells/mcL; Albumin: 4g/dl; TSH: 0.06 mU/L; fT4: 1.29 (L-T4 doses were 100 ug). Four months after parathyroid surgery, the intact PTH level dropped from 1602 ng/l to 550 (15–65 ng/L). Computed tomography and Tc-sestamibi scintigraphy - SPECT revealed a residual cervicothoracic mass in retroesophageal region (D1-D2) (Fig1 -2). The patient underwent a new surgery and the intact PTH dropped 39ng/L. Histopathology revealed characteristic features of a parathyroid adenomatous (10 gram weight) (Fig.3); additionally a retroesternal ectopic thyroid tissue. There was not reappearance of high blood calcium and parathormone levels more than 6 months after second surgery for PHPT. An unusual case of PHPT caused by a multiglandular disease parathyroid varies (four glands and a ectopic gland), reliable histopathologic adenomatous and hyperplastic parathyroid disease, and persistent primary hyperparathyroidism with very high serum intact PTH level.Reference: (1) Masi L. Primary Hyperparathyroidism. Brandi ML (ed): Parathyroid Disorders. Focusing on Unmet Needs. Front Horm Res. Basel, Karger, 2019, vol 51, pp 1–12. (2) Pecheva M, Mahendran K, Kadlec J, Lofthouse M1, Van Tornout F. Mediastinal giant parathyroid adenoma-a minimally invasive mediastinal surgical approach for an emergency presentation. Ann Cardiothorac Surg. 2016 Jan;5(1):70–3. (3) Cakmak H 1, Tokat AO, Karasu S, Özkan M. Adenoma paratiroideo mediastínico gigante. Tuberk Toraks. 2011; 59 (3): 263–5. (4)Thier M, Daudi S, Bergenfelz A, Almquist M. Predictors of multiglandular disease in primary hyperparathyroidism. Langenbecks Arch Surg. 2018;403(1):103–109.

Multiglandular Parathyroid Disease: the Results of Surgical Treatment

Background. Sporadic multiple gland disease in primary hyperparathyroidism occurs in 7 to 33 % of cases. The absence of specific risk factors, low sensitivity of imaging methods, and low efficiency of bilateral neck exploration and intraoperative monitoring of parathyroid hormone indicate the complexity of the diagnosis and treatment of this disease’s form. Aim of the research. To analyze the results of surgical treatment of multiple lesions of the parathyroid gland in primary and secondary hyperparathyroidism. Methods. There was retrospective study, which included 100 observations of surgical treatment for primary and secondary hyperparathyroidism in the thoracic department of Irkutsk Regional Clinical Hospital from May 2018 to September 2019. The main point was to identify the frequency of surgical treatment outcomes in patients with multiple parathyroid lesions. As part of the study, potential predictors of multiple gland disease in primary hyperparathyroidism were analyzed. Results. Multiple gland disease in primary hyperparathyroidism occurs in 29 % of cases and causes persistence of the disease (p ≤ 0.01). Signs of multiple gland disease in primary hyperparathyroidism include the level of ionized calcium, parathyroid hormone (p ≤ 0.05), creatinine level and glomerular filtration rate (p ≤ 0.01). A negative result of intraoperative monitoring correlates with persistence of primary hyperparathyroidism in multiple lesions (χ2, p ≤ 0.05). Selective parathyroidectomy is associated with persistence of hyperparathyroidism in multiple lesions (χ2, p ≤ 0.05), while total parathyroidectomy is associated with remission of the disease (χ2, p ≤ 0.05). We did not find a statistically significant relationship between the results of surgical treatment for morphology of the parathyroid glands (χ2, p &gt; 0.1). Conclusion. Multiple gland disease is the main cause of persistence of primary hyperparathyroidism. This form of the disease corresponds to lower levels of calcium, parathyroid hormone, and kidney function. Persistence factors have been established: removal of less than four parathyroid glands and a negative result of intraoperative monitoring of parathyroid hormone. Bilateral neck exploration does not reduce the incidence of disease persistence.

Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features.

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

Rare giant multiglandular parathyroid hyperplasia in type 1 multiple endocrine neoplasia assessed by sestamibi scintigraphy

We describe a rare case of 32-year-old male with multiple endocrine neoplasia type 1 (MEN1) gene mutation characterised by extensive parathyroid hyperplasia and pancreatic neuroendocrine tumour. Pre-operative Tc-99m Sestamibi scan showed multiple hyperfunctioning parathyroids which were confirmed intraoperatively to be giant hyperplastic glands and an ectopia in the mediastinum. According to the current guidelines, pre-operative imaging is of limited benefit in MEN1 parathyroid disease, nevertheless this case does demonstrate utility of preoperative Sestamibi scintigraphy in accurately estimating the extent of disease in MEN1. Consequently, it facilitates better surgical planning and decreases the chance of persistent disease.

Multiple endocrine neoplasia type 1 syndrome: single centre experience from western India.

Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare autosomal dominant familial cancer syndrome affecting multiple endocrine glands. Published literature on MEN1 from Indian subcontinent is scarce. We report here a case series of MEN1 patients (n=18) from 14 unrelated families. Retrospective study describing the clinical profile of MEN1 patients from endocrine unit of a tertiary care hospital from western India. Additionally clinical profile of primary hyperparathyroidism (PHPT) in MEN1 patients was compared with that of apparently sporadic PHPT cohort from our centre. Eighteen patients (10 males, 8 females) diagnosed as MEN1 were included. Mean age at diagnosis was 31.5±10.6years (range 17-54). Incidence of primary hyperparathyroidism (PHPT), pituitary adenoma (PA), and gastro-entero-pancreatic neuroendocrine tumor (GEP-NET) was 94.4, 72.2, and 72.2%, respectively. GEP-NET was the commonest presenting lesion (33.3%), followed by PA (27.7%), PHPT (16.6%), thymic carcinoid (5.5%), while 16.6% cases were identified on family screening. PHPT manifestations (clinical and biochemical) in MEN1 were less severe as compared to those of sporadic PHPT. Contrast enhanced computed tomography (CECT) and (68)Ga-DOTANOC PET/CT were equally sensitive (64.7 vs. 63.5%) in identifying multiglandular parathyroid disease. Non functioning tumors (NFT) were the most common GEP-NET, followed by insulinoma (5/13, two were metastatic). (68)Ga-DOTANOC PET/CT had higher sensitivity in detecting GEP-NET lesions than CECT (100 vs. 62.5%). The most common pituitary lesion was prolactinoma, and all were cabergoline responsive. Genetic analysis was available in 13 patients and 11 patients showed mutation in MEN1 gene. The clinical profile of MEN1 in Asian Indian patients is largely comparable to that reported in other cohorts. Peculiar findings of our cohort are predominance of GEP-NET as a presenting manifestation and relatively higher prevalence of insulinoma with higher occurrence of metastatic insulinoma. Clinical and biochemical profile of MEN1 associated PHPT is less severe than that of our sporadic PHPT.

Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4).

Inactivating germline mutations of the CDKN1B gene encoding the nuclear cyclin-dependent kinase inhibitor P27kip1 protein have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to characterize in vitro the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by primary hyperparathyroidism due to multiglandular parathyroid involvement and gastro–entero–pancreatic tumors. We carried out subcellular localization experiments by transfection with plasmid vectors expressing the WT or mutant CDKN1B cDNA into the eukaryotic human cervix adenocarcinoma (HeLa) and GH3 cell lines. Results from western blotting studies indicated that fusion proteins were expressed at equal levels. The mutated protein was shorter compared with the WT protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells, WT P27 localized in the nucleus, whereas the P27_S125X protein was retained in the cytoplasm, predicting the loss of tumor-suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, because both WT and mutant alleles were determined to be present by sequencing the somatic DNA. Immunohistochemistry revealed a complete loss of nuclear expression of P27 in a parathyroid adenoma, which had been removed by the second surgery in the patient. In conclusion, our results confirm the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.

Primary hyperparathyroidism in young people. When should we perform genetic testing for multiple endocrine neoplasia 1 (MEN-1)?

Multiple endocrine neoplasia (MEN-1) is a rare, autosomal dominant inherited disorder. Primary hyperparathyroidism (pHPT) is the most frequent and usually the earliest expression of MEN-1, with typical age of onset at 20-25 years. Early detection of the disease and correct treatment are therefore of great importance. A 31-year-old woman with osteogenesis imperfecta was incidentally found also to have hypercalcemia and elevated PTH (pHPT). Exploratory neck surgery showed multiglandular parathyroid affection; she turned out to have MEN-1, but she was diagnosed 7 years after her debut of pHPT. The aim was to search literature on indications for performing mutational analysis in young patients with pHPT and no family history of MEN-1. PubMed was searched for English language articles, and words used were: MEN1 OR MEN-1 OR MEN type 1 OR multiple endocrine neoplasia 1 OR multiple endocrine neoplasia type 1 AND Mutational analysis OR genetic testing OR testing OR Hyperparathyroidism, primary [majr]. A total of 625 abstracts were reviewed. Whether to perform screening of patients with pHPT under the age of 30, 35, or 40 years is controversial. According to international guidelines from 2001, genetic testing is indicated only in patients with pHPT below the age of 30 years. However, in updated guidelines from 2012, it is suggested to perform genetic testing in patients with pHPT below the age of 30 years, but also at any age in patients presenting with multigland parathyroid disease. The reviewed literature and the presented case illustrate the importance of this change in international guidelines, but they also raise concern for a potential underdiagnosing of patients before year 2012.

Dual-Isotope 99mTc-MIBI/123I Parathyroid Scintigraphy in Primary Hyperparathyroidism

In patients with primary hyperparathyroidism, the preoperative imaging objective is to locate accurately and reliably uniglandular or multiglandular hyperfunctioning parathyroid, to guide surgery, particularly for minimally invasive method. Subtraction planar scintigraphy with dual-isotope (I/Tc-MIBI) is an efficient examination to specify abnormal parathyroid location, but without accurate anatomic reference. This lack should be avoided by a hybrid SPECT/CT image acquisition. We compared planar scans (neck and mediastinum parallel-hole, associated with anterior neck pinhole) to neck and mediastinum SPECT/CT, all with subtraction (I/Tc-MIBI) method, in exact location of abnormal parathyroid in 50 patients with sporadic primary hyperparathyroidism. Surgical and histological findings were used as the standard of comparison. Sensitivity is equivalent for the 2 protocols (86% and 75% for SPECT/CT and planar protocol, respectively, P = 0.15), but SPECT/CT was highly specific (specificity 100% and 90% for SPECT/CT and planar protocol, respectively, P = 0.04). In patients with concomitant thyroid disease, subtraction SPECT/CT appeared to be more sensitive than planar protocol (88% and 62% for SPECT/CT and planar protocol, respectively, P = 0.04). In preoperative assessment of primary hyperparathyroidism and to guide surgery, we propose to perform first subtraction SPECT/CT and to complete it with neck pinhole, only if tomoscintigraphy is negative.