Following publication of the original article 1, the authors identified the following errors in the scientific content: p.4, para. 3: “(1 tablet/10 mL RIPA)” should read “(1 tablet/10 mL RIPA ...buffer)”. p.4, para. 4: “II-1” should read “II-2”. Minor mistakes were also identified in the table on page 6, and in the Abbreviations section on page 7. The original article has been corrected.
Purpose of Review
To summarize current evidence on the links between joint hypermobility (JH) and Ehlers-Danlos syndromes (EDS), with pain and reduced bone mass; to illustrate an updated approach to ...JH and EDS.
Recent Findings
In 2017, a novel classification for EDS and JH has been published. Increasing data demonstrate that pain is a major disability determinator in JH and EDS. Recent findings confirm a complex pathogenesis for pain in JH and EDS and suggest a potential role for joint instability, central sensitization and small fiber neuropathy. Some papers present bone mass reduction as an associated feature of JH and EDS. The association is preliminary and reflects heterogeneous mechanisms.
Summary
Assessment of patients with JH/EDS is now well-structured and based on an integrated approach of clinical evaluations and molecular testing. Pain and reduced bone mass are possibly common satellite manifestations of JH/EDS and need expert consult for appropriate interpretation and management.
Background The occurrence of parathyroid carcinoma in multiple endocrine neoplasia type I (MENI) is rare and the 15 cases of malignant parathyroid tumor reported so far have been associated with MENI ...in individuals and not with multiple members within a family. Methods We report on a 61-year-old male, operated for a 7.3 cm parathyroid carcinoma infiltrating the esophagus. In his brother, a 4.6 cm parathyroid carcinoma was diagnosed histologically, while in the daughter, neck ultrasonography revealed 2 extrathyroidal nodules, yet to be excised. Results Screening of the MEN1 gene identified a known germline heterozygous missense mutation (c.1252G>A; p.D418N) in exon 9, in all affected subjects. Conclusions The occurrence of parathyroid carcinoma in more than one affected member of a single MEN1 family represents the first reported familial case. This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.
Hemangioblastomas of the central nervous system (CNS) are benign neoplasms that may occur sporadically or in association with von Hippel-Lindau (VHL) disease. The proportion of primary symptomatic ...hemangioblastomas associated with VHL disease is estimated to be from 10 to 40%, but it seems to be underestimated. We investigated the frequency of VHL germline mutation in patients with symptomatic CNS hemangioblastoma without evidence of VHL disease to define the role of molecular genetic analysis in the management of such patients and their relatives.
We analyzed 14 patients (6 female and 8 male; mean age, 43.5 yr) with no family history and no other clinical manifestations of VHL disease who had been operated on for symptomatic CNS hemangioblastoma. Exons 1, 2, and 3 of the VHL gene and their immediately flanking sequences were amplified by use of polymerase chain reaction followed by analysis with denaturing high-performance liquid chromatography and sequencing the anomalous samples.
Germline mutations of the VHL gene were identified in 2 (14%) of 14 patients. VHL gene mutation analysis was performed in both patients' family members, which showed another affected asymptomatic subject for VHL disease. The affected subjects were recommended for VHL disease surveillance protocol.
Molecular genetic analysis is a safer and more specific instrument to confirm or exclude VHL disease in patients with CNS hemangioblastoma, a negative family history, or absence of other known manifestations of the disease. Early identification of VHL mutation gene carriers is important for reducing disease morbidity and mortality. Nonsymptomatic family members will benefit from early VHL disease diagnosis or by being excluded as at-risk subjects, reducing the psychological and economic burden of screening and surveillance protocols.
Although there is general agreement on the methods of treatment for symptomatic supratentorial cerebral cavernous malformations (CMs) located in noneloquent areas, some controversy exists regarding ...the management of cerebral CMs that are asymptomatic and/or located in eloquent or deep areas. Moreover, recent advances in genetic findings could influence both standard clinical management and the follow-up strategy in affected individuals. Thus, the objective of this study was to develop, based on the authors' experience and a literature review, a management algorithm to deal with supratentorial cerebral CMs.
The authors retrospectively reviewed the clinical data related to 118 patients who underwent surgery for symptomatic supratentorial cerebral CMs at their institution. Twenty-eight of 118 patients harbored multiple lesions, and nine of these 28 patients had a clinically positive familial history. Genetic investigations were performed in 89 patients (75%).
Surgery for supratentorial cerebral CMs in noneloquent locations is safe and curative. In cerebral CMs located in deep and eloquent areas and with symptoms including progressive neurological deficits, evidence of hemorrhage, and uncontrolled seizures, surgical treatment according to an integrated plan based on frameless stereotactic guidance and functional magnetic resonance imaging is recommended and results in acceptably low morbidity. The data support the need for long-term imaging follow up in all patients, careful preoperative vascular studies to detect associated venous anomalies, and the importance of genetic mutational analysis. The DNA screening protocol will change the care of family members of patients with familial forms of cerebral CMs, because affected asymptomatic family members may benefit by early detection of lesions. At the same time, the exclusion of family members who are not carriers of the mutation as members of the population at risk reduces the economic and psychological burden of clinical and instrumental monitoring.
Parathyroid tumors are common endocrine neoplasias associated with primary hyperparathyroidism, a metabolic disorder characterized by parathormone hypersecretion. Parathyroid neoplasia are frequently ...benign adenomas or multiple glands hyperplasia, while malignancies are rare. The epigenetic scenario in parathyroid tumors has just begun to be decoded: DNA methylation, histones and chromatin modifiers expression have been investigated so far. The main findings suggest that DNA methylation and chromatin remodeling are active and deregulated in parathyroid tumors, cooperating with genetic alterations to drive the tumor phenotype: the tumor suppressors menin and parafibromin, involved in parathyroid tumorigenesis, interact with chromatin modifiers, defining distinct epigenetic derangements. Many epigenetic alterations identified in parathyroid tumors are common to those in human cancers; moreover, some aspects of the epigenetic profile resemble epigenetic features of embryonic stem cells. Epigenetic profile may contribute to define the heterogeneity of parathyroid tumors and to provide targets for new therapeutic approaches.
•Parathyroid tumors display hypermethylation of the CpG islands in the promoter of specific genes.•Hypermethylation occurs mainly in aggressive and malignant parathyroid tumors.•Parathyroid pivotal genes are not regulated by DNA methylation.•The tumor suppressor genes lost in parathyroid tumorigenesis interact with a number of chromatin modifiers.•Chromatin modifiers deregulation in parathyroid tumors is similar to that in human cancers and in embryonic stem cells.
Parathyroid carcinoma Salcuni, Antonio Stefano; Cetani, Filomena; Guarnieri, Vito ...
Baillière's best practice & research. Clinical endocrinology & metabolism,
December 2018, 2018-12-00, Letnik:
32, Številka:
6
Journal Article
Recenzirano
Parathyroid carcinoma (PC) is a rare disease with an indolent behavior due to the low malignant potential. The etiology is unknown. Somatic mutations of CDC73 gene, the same gene involved in the ...hyperparathyroidism-jaw tumor syndrome, can be identified in up to 70% of patients with PC and in one-third of cases the mutations are germline. Therefore, in patients who carry germline CDC73 gene mutations, its finding permits to identify the carriers among relatives and sometimes to early detect a parathyroid lesion in such subjects. The diagnosis of PC is commonly made after surgery, however there are some clinical/biochemical features that should raise the suspicion of PC, namely markedly elevated serum calcium and PTH levels, a large parathyroid lesion with suspected ultrasonographic features of malignancy, the damages of kidney and bones. The best chance of cure is the complete surgical resection with the en-bloc excision at the first operation, however several recurrences are often observed during the follow-up. Since PC is an indolent tumor with long-lasting survival and the death is due to complications of untreatable hypercalcemia, multiple surgical interventions with debulking of tumoral tissues along with medical treatment for reducing hypercalcemia are often needed. Patients with PC should be followed up along their lifetime.
To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (
MEN1
) and type 2 (
MEN2
) genes in a large Italian family and evaluate if it could be associated with more ...aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The
RET
gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the
MEN1
coding regions, including the exon–intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of
RET
proto-oncogene and the second one, IVS4+1G>T, located in the
MEN1
gene. The functional characterization of IVS4+1G>T variation, located in the splicing donor site of exon 4 of
MEN1
gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband’s germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G>T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both
RET
proto-oncogene and
MEN1
gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases.
Molecular pathogenesis of parathyroid tumours Cinque, Luigia; Pugliese, Flavia; Salcuni, Antonio Stefano ...
Baillière's best practice & research. Clinical endocrinology & metabolism,
December 2018, 2018-12-00, Letnik:
32, Številka:
6
Journal Article
Recenzirano
Parathyroid tumors represent an elusive endocrine neoplasia, which lead to primary hyperparathyroidism, pHPT, a common endocrine calcium disorder characterized by hypercalcemia and normal-high ...parathormone secretion. Parathyroid tumours are benign adenomas or multiple glands hyperplasia in the vast majority (>99% of cases), while malignant neoplasms are rare (less than 1%). Despite pHPT is a common disorder, our knowledge about the genetic predisposition and molecular pathophysiology is limited to the familial syndromic forms of parathyroid tumour, that, however, represent not more than the 10% of all the cases; instead, the pathophysiology of sporadic forms remains an open field, although data about epigenetic mechanisms or private genes have been supposed.
Here we present an overview of more recent acquisitions about the genetic causes along with their molecular mechanisms of benign, but also, malignant parathyroid tumours either in sporadic and familial presentation.
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