Search

The most common causes of hypercalcemia are primary hyperparathyroidism (PHPT) and malignancy. Parathyroid carcinoma (PC), causing a severe PHPT, is the rarest parathyroid tumor. A diagnosis of PC is challenging because the clinical profile overlaps with that of benign counterpart. Surgery is the mainstay treatment. CDC73 mutations have been detected in up to 80% of sporadic PCs. Ectopic production of parathyroid hormone (PTH) by malignant nonparathyroid tumors is a rare condition accounting for less than 1% of hypercalcemia of malignancy. PTH secretion can be considered an aberration in the tissue specificity of gene expression and may involve heterogeneous molecular mechanisms.

Background/aim The lack of specific parathyroid carcinoma (PC) biomarkers in clinical practice points out the importance of analyzing the proteomic signature of this cancer. We performed a comparative proteomic analysis of PC and parathyroid adenoma (PA) co-existing in the same patient. Patients and methods PC and PA were taken from a 63-year-old patient. Using two-dimensional differential gel electrophoresis (2D-DIGE) coupled to mass spectrometry we examined the differences between PC and PA proteins. For validation, additional PC and PA samples were obtained from 10 patients. Western blot analysis was used to validate the difference of expression observed with 2D-DIGE analysis. Bioinfomatic analysis was performed using QIAGEN's Ingenuity Pathways Analysis (IPA) to determine the predominant canonical pathways and interaction networks involved. Results Thirty-three differentially expressed proteins were identified in PC compared to PA. Among these, ubiquitin C-terminal hydrolase-L1 (UCH-L1) was highly overexpressed in PC. The result was confirmed by Western Blot analysis in additional PC samples. Conclusion Our comparative proteomic analysis of co-existing neoplasms allowed detecting specific and peculiar differences between PC and PA overcoming population biological variability.

Context The pathogenesis of nephrolithiasis in primary hyperparathyroidism (PHPT) remains to be elucidated. The latest guidelines suggest parathyroidectomy in patients with asymptomatic PHPT with hypercalciuria (> 400 mg/d) and increased stone risk profile. Objective The objective of this work is to evaluate the association of urinary stone risk factors and nephrolithiasis in patients with asymptomatic sporadic PHPT and its clinical relevance. Design A total of 157 consecutive patients with sporadic asymptomatic PHPT were evaluated by measurement of serum and 24-hour urinary parameters and kidney ultrasound. Results Urinary parameters were tested in the univariate analysis as continuous and categorical variables. Only hypercalciuria and hypomagnesuria were significantly associated with nephrolithiasis in the univariate and multivariate analysis adjusted for age, sex, body mass index, estimated glomerular filtration rate, parathyroid hormone, 25-hydroxyvitamin D, serum calcium, and urine volume (odds ratio, OR 2.14 [1.10-4.56]; P = .04; OR 3.06 [1.26-7.43]; P = .013, respectively). Hypomagnesuria remained associated with nephrolithiasis in the multivariate analysis (OR 6.09 [1.57-23.5], P = .009) even when the analysis was limited to patients without concomitant hypercalciuria. The urinary calcium/magnesium (Ca/Mg) ratio was also associated with nephrolithiasis (univariate OR 1.62 [1.27-2.08]; P = .001 and multivariate analysis OR 1.74 [1.25-2.42], P = .001). Hypomagnesuria and urinary Ca/Mg ratio had a better, but rather low, positive predictive value compared with hypercalciuria. Conclusions Hypomagnesuria and urinary Ca/Mg ratio are each associated with silent nephrolithiasis and have potential clinical utility as risk factors, besides hypercalciuria, for kidney stones in asymptomatic PHPT patients. The other urinary indices that have been commonly thought to be associated with kidney stones in PHPT are not supported by our results.

La Sindrome delle Neoplasie Endocrine multiple (MEN) di tipo 4 (MEN4) si e configurata nell’ultimo decennio come una variante geneticamente distinta dalle tipologie precedentemente note di MEN (MEN1, MEN2A, MEN2B) che condividono con essa la predisposizione allo sviluppo di tumori multipli endocrini e non. L’identificazione della causa molecolare (mutazioni germinali del gene Cdkn1b) di una variante di MEN insorta spontaneamente in una colonia di ratti, chiamata MENX, in cui gli animali sviluppavano uno spettro di tumori endocrini tipici sia della MEN1 che della MEN2 umane, ha condotto alla ricerca di mutazioni germinali del gene CDKN1B umano, codificante per P27, un inibitore della progressione del ciclo cellulare, nei pazienti che presentavano caratteristiche fenotipiche della MEN1 o MEN2 ma negativi per le mutazioni dei geni MEN1 e RET, rispettivamente. Ad oggi sono stati identificati 23 casi di MEN4; alcuni di essi presentano una storia familiare di tumori endocrini, mentre altri sembrano essere apparentemente sporadici. Considerata la variabilita fenotipica dei pazienti e il numero esiguo dei casi descritti in letteratura non e possibile attualmente definire un quadro clinico tipico della MEN4. Non essendo state redatte, ad oggi, linee guida con raccomandazioni cliniche utili per la diagnosi e il trattamento di questi casi, ai pazienti con fenotipo MEN1-like con test genetico negativo per MEN1 e RET viene offerto lo screening genetico di CDKN1B e il trattamento dei tumori associati.

Context Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH. Objective To describe a cohort of 26 patients with PHP followed in a single tertiary center. Methods Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002. Results Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium–phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort. Conclusion Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.

ContextAtypical parathyroid adenomas (APAs) are neoplasms with uncertain malignant potential but lack unequivocal histological signs of malignancy.ObjectiveThis work aims to retrospectively evaluate the clinical and biochemical profiles of patients with APA, the outcome after parathyroidectomy (PTX), and the presence of CDC73 germline and somatic mutations.MethodsThis monocentric study was conducted on consecutive patients undergoing PTX for primary hyperparathyroidism (PHPT) between June 2000 and December 2020. Fifty-eight patients with a confirmed histopathological diagnosis of APA, and age- and sex-matched controls with parathyroid adenoma (PA) were also included.ResultsFifty-four patients had sporadic PHPT and 4 had familial isolated hyperparathyroidism (FIHP). Thirty-four patients (59%) had symptomatic disease. Serum calcium and parathyroid hormone (PTH) levels were significantly higher in symptomatic compared to asymptomatic patients (P = .048 and .008, respectively). FIHP patients were younger than their sporadic counterparts (30 ± 17 years vs 55 ± 13 years). APA patients had significantly higher serum calcium and PTH levels and lower 25-hydroxyvitamin D concentration, bone mineral density, and T score at one-third distal radius compared to those with PA. Four of 56 APA patients displayed a CDC73 germline mutation. No somatic CDC73 mutation was identified in 24 tumor specimens. The mean follow-up after surgery was 60 ± 56.4 months. All but 6 patients (90%), 5 with apparently sporadic PHPT and 1 with FIHP, were cured after surgery.ConclusionThe large majority of patients with APA, despite a moderate/severe phenotype, have a good prognosis. Germline CDC73 mutation–positive patients had a higher rate of persistent/recurrent disease. CDC73 gene alterations do not seem to have a relevant role in the tumorigenesis of sporadic APA.

Purpose: Previously in 1987, a 21-year-old-male was diagnosed with primary hyperparathyroidism (PHPT) when a right inferior parathyroid adenoma was removed. PHPT recurred after three and six years and on both occasions was cured by resection of parathyroid adenomas. At 52-years-of-age, the patient developed a late-onset hypoparathyroidism (HP), even though postsurgical HP typically occurs as a transient or permanent form soon after neck surgery. The purpose of this work was to report the follow-up of the patient and to review prior cases of late-onset postsurgical HP.\ud \ud Methods: Prior cases of late-onset postsurgical HP were searched and reviewed focusing on clinical and biochemical features.\ud \ud Results: The patient’s asymptomatic hypocalcemia with total serum calcium at 8.2 mg/dL was initially documented in September 2018; PTH was inappropriately low at 15 ng/mL. In\ud February 2020, a mild hypocalcemia was confirmed with low-normal PTH at 15 ng/mL. Autoimmune and familial causes of HP were ruled out including the presence of stimulating autoantibodies against calcium-sensing receptor. Instead, a progressive damage or atrophy of the parathyroid gland(s) ensuing years after surgery is believed to have led to the patient’s hypocalcemia. All 19 previously reported cases of late-onset postsurgical HP occurred after thyroid surgery, with no examples of the condition being found following parathyroidectomy.\ud \ud Conclusions: The case highlights the rare occurrence of late-onset postsurgical HP in a patient who had had multiple parathyroidectomies for PHPT. Thus, monitoring serum calcium,\ud phosphate and PTH during follow-up of such patients is recommended.

The 4th International Workshop for the management of asymptomatic PHPT included, among the criteria for parathyroidectomy, the presence of hypercalciuria (dUCa> 400 mg/day) and increased biochemical stone risk profile. The aim of the present study was to evaluate the biochemical stone risk profile in 176 consecutive patients (143 females and 33 males) with asymptomatic PHPT. We recorded clinical and biochemical data, including 24 hours urinary measurements of the following parameters: volume and pH, creatinine, calcium, magnesium, sodium, potassium, ammonium, uric acid, oxalate, citrate, phosphate, inorganic sulphate and chloride and kidney ultrasound. In our cohort dUCa> 400mg/day showed a low sensitivity and positive predictive value (PPV) for nephrolithiasis with high specificity (46.2, 32.7, 73.0% respectively), while hypercalciuria by 4 mg/kg/bw (d-UCa>4mg/kg) had a high sensibility, with low PPV and specificity (79.5, 27.7, 40.1%) Daily hypomagnesuria (d-HypoMg), but not any other urinary parameter, was an independent predictor of nephrolithiasis in the univariate (OR 2.97 CI 1.27-7.09 P=0.014) and multivariate analyses adjusting for age, sex, BMI, and eGFR (OR 3.13 CI 1.17-8.42 P=0.02). d-HypoMg was relatively lower in the regression analysis with urinary calcium in patients with nephrolithiasis compared with those without. The mean ratio between (dUCa) and (dUMg) was higher in patients with nephrolithiasis compared with those without (4.6±2.0 vs 3.3±4.1; P In patients with hypercalciuria (>400 mg/24-hour) dUMg was positively correlated with dUCa in those without nephrolithiasis (r=0.50, β=0.2, P=0.002) but not in those with nephrolithiasis (r=0.05, β= 0.014; P=0.8). In patients without hypercalciuria we found that hypomagnesuria remained a predictor of nephrolithiasis using either 400 mg/die (P=0.002, OR 5.12 (1.84-14.24) or 4 mg/kg bw (P=0.014, OR 6.24 (1.45-26.8). Moreover, the OR for nephrolithiasis improved using the combination of d-HypoMg with d-UCa>4mg/kg (OR 8.12, CI 1.92-34.18, P=0.004), but not with dUCa> 400mg/day. The current urinary calcium threshold of >400 mg/24-hour has a low sensitivity in detecting nephrolithiasis; our data suggest that sensitivity, specificity and positive predictive value could be improved including dUMg, dUCa/dUMg ratio and the combination of d-HypoMg with d-UCa>4mg/kg in the stone risk evaluation.

Unfortunately, the 13th author name has been published incorrectly in the original publication.

Objectives The aims of this paper were to evaluate the levels of Vitamin D (VitD) in patients with heart failure (HF), compared to a control group, to assess the effects of VitD on HF outcome and to compare VitD measurement between LIAISON immunoassay and HPLC-MS-MS methods in this population. Design and Methods We collected clinical, biochemical and outcome data from 247 patients with HF and in a subgroup of 151 patients, we measured VitD both with LIAISON and HPLC-MS-MS. Results HF patients had statistically lower 25OHD levels (45.2 ± 23.7 nmol/L vs 58.2 ± 24.0 nmol/L, P P P P = 0.02), confirmed in a multivariate adjusted analysis. Kaplan–Meier survival analyses showed that VitD insufficiency was associated with reduced survival in HF patients (log rank P = 0.017). There was a good agreement between LIAISON and HPLC-MS-MS (Cohen’s kappa coefficient 0.70), but the prevalence of VitD insufficiency was significantly higher with the former compared to the latter method (58.3%, n = 88 vs 55.6%, n = 84, P Conclusions 25OHD levels adequately measured by HPLC-MS-MS showed to be low in HF population and to be correlated with HF-related risk of death.

The latest guidelines of the 4th International Workshop on Asymptomatic Primary Hyperparathyroidism (aPHPT) reintroduced hypercalciuria (i.e. urinary calcium > 400 mg/day) as criterion for surgery. However, the value of hypercalciuria as a predictor of nephrolithiasis and the correct cut-off values still need to be confirmed. To evaluate the prevalence of silent kidney stones in a large series of patients with aPHPT and the sensibility, specificity and predictive value of different cut-off values of hypercalciuria in identifying patients with nephrolithiasis. One hundred seventy-six consecutive patients with aPHPT were evaluated at our Institution by serum and urinary parameters and kidney ultrasound. Silent nephrolithiasis was found in 38 (21.6%) patients. In the univariate and multivariate model, hypercalciuria was a predictor of nephrolithiasis using the criterion of 400 mg/24 h [(OR 2.30, (1.11–4.82) P = 0.025], 4 mg/kg/bw [OR 2.65, (1.14–6.25) P = 0.023], gender criterion [OR 2.79, (1.15–6.79) P = 0.023] and the cut-off value derived from the ROC analysis [(> 231 mg/24 h) OR 5.02 (1.68–14.97) P = 0.004]. Despite these several predictive criteria, however, hypercalciuria had a low positive predictive value (PPV), ranging from 27.4 to 32.7%. Hypercalciuria is a predictor of nephrolithiasis, but its PPV is low.

Atypical parathyroid adenomas represent a group of intermediate form of parathyroid neoplasms of uncertain malignant potential which show some atypical histological features that represent a challenge for the differential diagnosis with parathyroid carcinomas. They may occur as sporadic or as a part of hereditary syndromes. The molecular signature of these neoplasms is still unknown and the germline CDC73 mutations appears to be the most common anomaly in this setting suggesting that these cases might represent variants of the hyperparathyroidism-jaw tumor syndrome. The identification of markers predicting the outcome is of great importance to guide an adequate postoperative monitoring and, the same time, relieve of the anxiety of relatively strict monitoring patients not at risk. This review will summarize the current knowledge of the clinical, biochemical, molecular and histological profile of atypical parathyroid adenomas.

Parathyroid carcinoma (PC) is a rare neoplasia difficult to diagnose preoperatively. It mainly occurs as a sporadic disease but also as part of familial PHPT. At variance with patients with the benign counterpart, the phenotype of these patients is characterized by a severe primary hyperparathyroidism (PHPT). The clinical features are mostly due to the effects of the excessive secretion of PTH by the functioning tumor and hypercalcemia rather than to the tumor burden. The prognosis is poor and unmanageable hypercalcemia accounts for death in the majority of cases. The best chance of cure is surgery, although persistent or recurrent disease occurs in about 50% of patients. Somatic loss-of-function mutations of CDC73 gene, encoding parafibromin, are the most frequent genetic alterations occurring in PCs. Mutations of the PRUNE2 gene, alterations of the PI3K/AKT/mTOR pathway and amplification of the CCND1 gene have been recently detected in PCs. Alteration of microRNA profile and methylation pattern have been identified in PCs. The recent studies have better defined the genomic landscape of PCs and represent major progress toward a full molecular characterization of this neoplasia and development of novel therapeutic options.

Juvenile primary hyperparathyroidism is uncommon and more symptomatic than the adult counterpart. The aim of this prospective monocentric study, conducted in a tertiary referral center, was to evaluate the clinical, biochemical, and densitometric data, and the outcome of a series of patients with juvenile primary hyperparathyroidism. The study group included 154 patients with sporadic and familial juvenile primary hyperparathyroidism, aged ≤40 years. Relative frequency of sporadic and familial forms, comparison of the clinical and biochemical characteristics, rate of cure after parathyroidectomy and the outcome of patients not undergoing surgery were evaluated. Familial cases (n = 42) were younger, less frequently females, and had milder disease compared to sporadic cases (n = 112). No difference was observed in biochemical and densitometric parameters. Among patients undergoing parathyroidectomy (n = 116), familial cases had a higher rate of multigland disease and a higher persistence/relapse rate compared to sporadic cases (73 vs. 3.6% and 48.1 vs. 5.7%, respectively). Patients who did not undergo parathyroidectomy had stable clinical, biochemical, and densitometric parameters during follow-up (median 27 months). Using the cut-off age of 25 years, there was no difference in clinical, biochemical and densitometric parameters between younger and older patients, with the exception of parathyroid hormone and phosphate, which were significantly lower and higher, respectively, in patients

We describe a 45-yr-old woman with metastatic breast cancer and hypercalcemia previously diagnosed as hypercalcemia of malignancy and treated with bisphosphonates without changes of serum calcium (s-Ca). At the time of our evaluation, biochemical data [s-Ca, 10.8 mg/dl (2.70 mmol/liter); PTH, 24.4 pg/ml (2.6 pmol/liter); 24-h urinary calcium, 160 mg (4.0 mmol); calcium/creatinine clearance, 0.007] suggested the diagnosis of familial hypocalciuric hypercalcemia. Three of five relatives had mild hypercalcemia [s-Ca, 10.7–11.2 mg/dl (2.67–2.80 mmol/liter)] and detectable serum PTH [24.5–29.0 pg/ml (2.6–3.1 pmol/liter)]. A novel heterozygous I212T missense mutation in exon 4 of the calcium-sensing receptor (CaR) gene was found in the proband and affected relatives but not in unaffected relatives. Expression of the mutant I212T CaR in COS-7 cells resulted in no response of inositol phosphates to any calcium concentration. The calcium dose-response curve of the coexpressed receptors [wild-type/I212T] suggested that the mutant receptor interferes with the function of the wild-type receptor. In conclusion, we describe a case of familial hypocalciuric hypercalcemia due to a novel CaR mutation, in a woman with breast cancer in whom hypercalcemia was initially attributed to hypercalcemia of malignancy.

OBJECTIVE: Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. DESIGN: The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). METHODS: A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. RESULTS: The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. CONCLUSIONS: Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.

Inactivating mutations of the CDC73 tumor suppressor gene have been reported in parathyroid carcinomas (PC), in association with the loss of nuclear expression of the encoded protein, parafibromin. The aim of this study was to further investigate the role of the CDC73 gene in PC and evaluate whether gene carrier status and/or the loss of parafibromin staining might have an effect on the outcome of the disease. We performed genetic and immunohistochemical studies in parathyroid tumor samples from 35 patients with sporadic PC. Nonsense or frameshift CDC73 mutations were detected in 13 samples suitable for DNA sequencing. Six of these mutations were germline. Loss of parafibromin expression was found in 17 samples. The presence of the CDC73 mutation as well as the loss of parafibromin predicted a high likelihood of subsequent recurrence and/or metastasis (92.3%, P=0.049 and 94.1%, P=0.0017 respectively), but only the latter was associated with a decreased overall 5- and 10-year survival rates (59%, P=0.107, and 23%, P=0.0026 respectively). The presence of both the CDC73 mutation and loss of parafibromin staining compared with their absence predicted a lower overall survival at 10- (18 vs 84%, P=0.016) but not at 5-year follow-up. In conclusion, loss of parafibromin staining, better than CDC73 mutation, predicts the clinical outcome and mortality rate. The added value of CDC73 mutational analysis is the possibility of identifying germline mutations, which will prompt the screening of other family members.

Background Diagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1. Case presentation The patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed “adenoma-like” kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence. Conclusions Despite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

Multiple endocrine neoplasia (MEN) are clinical inherited syndromes affecting different endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. HeterozygousMEN 1germline mutations have been detected in about 70–80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the endocrine neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of theRETprotooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specificRETmutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target theRETpathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment.

Bone morbidity remains a major problem even after successful renal transplantation. We investigated the role of calcium-sensing receptor (CaSR) polymorphisms and 25-hydroxyvitamin D levels on the persistence of secondary hyperparathyroidism (SHPT) and their relationships with vertebral fractures (VFx) in 125 renal allograft recipients transplanted 44 ± 23 months before. All patients underwent evaluation of the main biochemical parameters of calcium metabolism as well as vertebral and femoral bone density. In 87 patients, CaSR polymorphisms (A986S, R990G, and Q1011E) also were assessed. X-ray images of the lateral spine were obtained in 102 subjects to perform vertebral morphometry. High parathyroid hormone (PTH) and 25-hydroxyvitamin D lower than 80 nmol/L were found in 54% and 97% of patients, respectively, with 40% of these showing vitamin D levels lower than 30 nmol/L. VFx were detected in 57% of the subjects. After multiple adjustments, 25-hydroxyvitamin D, age, and hemodialysis duration, but not CaSR polymorphisms, were found to be significant predictors of high PTH, whereas age and time since transplant were positively related with lower 25-hydroxyvitamin D values. PTH and time since transplant were significantly associated with VFx. Patients with two or more VFx showed serum PTH levels 50% higher than patients without fractures. We therefore conclude that persistent SHPT is a very common feature after renal transplantation and that, unlike CaSR polymorphisms, low 25-hydroxyvitamin D is involved in its pathogenesis. High PTH levels, in turn, are associated with an increased VFx risk, which confirms the need for strategies aimed at lowering serum PTH in this setting as well. © 2010 American Society for Bone and Mineral Research.

HRPT2 and parafibromin studies improved the diagnostic accuracy in two patients with primary hyperparathyroidism (PHPT) referred to us after surgery, in whom the clinical data were at variance with the pathological diagnosis of adenoma and carcinoma, respectively. Patients were referred to us after parathyroidectomy. Patient #1 had had a 1.5-cm tumor easily removed with a histological diagnosis of parathyroid carcinoma and normocalcemia for 2 years. Re-examination of the histology showed no cardinal signs of parathyroid cancer. Patient #2, with severe PHPT, had had the removal of a 3.5-cm tumor described histologically as adenoma. Ten years later PHPT recurred and persisted despite removal of two mildly enlarged parathyroid glands that were histologically normal. Re-review of the initial histology showed a trabecular pattern, fibrous bands, and atypical mitoses, suggesting an atypical adenoma. Because of the suspicion that case #1 could be an atypical adenoma and case #2 a carcinoma further molecular studies were performed. No HRPT2 and parafibromin abnormalities were identified in patient #1, strongly indicating a benign lesion. In patient #2, an HRPT2 germline mutation was found (E115X in exon 4) and associated with no parafibromin staining. These data, together with the clinical features, supported the suspicion of a parathyroid carcinoma that was confirmed by histological examination of further slides of the tumor, showing capsular and vascular invasion. A lung 1.5-cm nodule detected by computed tomography was excised. Histology showed a metastasis of parathyroid carcinoma. HRPT2 gene studies improved the diagnostic accuracy in 2 parathyroid tumors that are of uncertain type.

Summary Objective Familial isolated primary hyperparathyroidism (FIPH) can result from either incomplete expression of a syndromic form of familial primary hyperparathyroidism [multiple endocrine neoplasia type 1 (MEN 1), hyperparathyroidism–jaw tumour syndrome (HPT-JT) or familial hypocalciuric hypercalcaemia (FHH)] or still unrecognized causes. Design Genetic analyses of MEN1, HRPT2 and CASR genes in FIHP. Patients Seven well-characterized Italian kindreds with FIHP, with negative clinical features for MEN 1, HPT-JT and FHH. The mean age (± SD) at diagnosis was 45 ± 17 years (range 18–70 years) in the probands and 42 ± 18 years (range 15–69 years) in the other affected subjects. Measurements Direct sequencing of germline DNA of the MEN1, HRPT2 and CASR genes from probands. The region of interest was amplified in some family members. Results Germline MEN1 mutations were detected in three kindreds. Multiglandular involvement was found in all but one affected subject belonging to the three kindreds with MEN1 mutations. In these patients persistence/relapse of the disease was observed unless an extensive parathyroidectomy (excision of 31/2 glands) had been performed, with the exception of one patient, who is currently normocalcaemic 168 months after excision of two glands. No mutations of MEN1, HRPT2 and CASR genes were identified in the remaining four families. Conclusions MEN1 genotyping appears worthwhile in FIHP families, as the finding of mutation(s) may predict multiglandular involvement and therefore have practical surgical implications, and prompt further investigation in the family, with the possibility of identifying new cases and beginning a programme of periodic surveillance for emergence of tumours in all carriers.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder characterized by hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis, and ectodermal dystrophies and other organ-specific autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is caused by mutations of the autoimmune regulator gene. We identified an Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and a pattern of inheritance suggestive of a dominant mechanism. Serological and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classical autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Direct sequencing of the entire coding region of the autoimmune regulator gene revealed the presence in the proband of a novel missense (G228W) mutation in exon 6 in a heterozygous state. The same heterozygous mutation was identified in all family members with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and/or hypothyroid autoimmune thyroiditis. None of the unaffected family members and 50 unrelated Italian controls carried the mutation. In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in our family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the hypothyroid autoimmune thyroiditis/polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype to the offspring in each generation in the absence of consanguinity, further supporting a dominant inheritance. The G228W closely cosegregated with hypothyroid autoimmune thyroiditis in our family, whereas a low penetrance of the full autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype was observed. In conclusion, we report a novel mutation of the autoimmune regulator gene in a family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, closely cosegregating with hypothyroid autoimmune thyroiditis. The G228W mutation acts in a dominant fashion and may shed light on the structure-function relationship of the autoimmune regulator protein.