GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.

CONTEXT: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. OBJECTIVE: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. DESIGN AND PATIENTS: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. RESULTS: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). CONCLUSIONS: Observed in vitro-activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.

Are otolaryngology residents ready for independent practice? A survey study.

OBJECTIVE: We surveyed otolaryngology program directors (PDs) and recent otolaryngology residency graduates on the operative autonomy of graduating residents and their comfort with independent practice. METHODS: An anonymous survey was sent to otolaryngology PDs and recent graduates of training programs (members of the Young Physicians Section [YPS] of the American Academy of Otolaryngology-Head and Neck Surgery Foundation). Questions were developed around the 14 key indicator procedures (KIPs) defined by the Accreditation Council for Graduate Medical Education. RESULTS: Fifty PDs (43% of PDs) and 152 recent graduates (6% of YPS members) responded. Over 90% of participating PDs felt their graduating residents were either somewhat or extremely comfortable performing 12 out of 14 KIPs. Among the 12 procedures PDs felt their graduating residents were comfortable performing, 57% to 95% of recent graduates also felt either somewhat or extremely comfortable performing them by graduation. Similarly, at least 90% of responding PDs felt their residents achieved meaningful autonomy in the last 2 months of residency prior to graduation for 11 of 14 KIPs. For these same 11 procedures, 74% to 95% of recent graduates indicated they achieved meaningful autonomy. The procedures that PDs and recent graduates felt required the most surgical assistance were ossiculoplasty/stapedectomy, rhinoplasty, and mastoidectomy. All PDs agreed or strongly agreed that graduating residents are comfortable operating and taking call as general otolaryngologists, compared to 86% and 93% of recent graduates. CONCLUSION: Most PDs and recent graduates agree that residents are well-prepared for general otolaryngology practice with the exception of select KIPs.Level of evidence: 4.

Continuation of telemedicine in otolaryngology post-COVID-19: Applications by subspecialty.

OBJECTIVE: The purpose of this paper is to review the literature and compile key clinically relevant applications of telemedicine for use in otolaryngology relevant to the post-COVID-19 era. STUDY DESIGN: Systematic Literature Review. DATA SOURCES: Pubmed and Google Scholar. REVIEW METHODS: Pubmed and Google Scholar were queried using combined key words such as "telemedicine," "covid" and "otolaryngology." The searches were completed in March-August 2020. Additional queries were made with particular subspecialty phrases such as "rhinology" or "otology" to maximize yield of relevant titles. Relevant articles were selected for abstract review. Applicable abstracts were then selected for review of the full text. RESULTS: Initial search identified 279 results. These were screened for relevance and 100 abstracts were selected for review. Abstracts were excluded if they were not in English, not related to otolaryngology, or if the full text was unavailable for access. Of these, 37 articles were selected for complete review of the full text. CONCLUSION: The sudden healthcare closures during the COVID-19 pandemic resulted in a sharp increase in the use of telemedicine, particularly in subspecialty fields. Otolaryngologists are at a unique risk of infection resulting from the examination of the head and neck and aerosol-generating procedures due to the predilection of viral particles for the nasal cavities and pharynx. The COVID-19 pandemic may have served as a catalyst to implement telemedicine into clinical practice, however identifying ways to integrate telemedicine long term is key for a sustainable and viable practice in the post-COVID-19 era. Although many states are now finding themselves on the down-sloping side of their infection rate curve, many others remain at the apex. Additionally, the risk of future waves of this pandemic, or the onset of another pandemic, should not be overlooked. Practice modification guidelines that mitigate infection risk by utilizing telemedicine would be useful in these instances. Telemedicine can help to reduce infection spread by limiting unnecessary in-person interactions and help conserve personal protective equipment (PPE) by facilitating remote care with the added benefits of expanding care to broad geographic areas, limiting cost, time, and travel burden on patients and families, and enabling consistent follow up.

PIK3CA Mutational Analysis of Parathyroid Adenomas.

Benign parathyroid adenoma is the most common cause of primary hyperparathyroidism, whereas malignant parathyroid carcinoma is exceedingly rare. Distinguishing parathyroid carcinoma from benign adenoma is often difficult, and may be considerably delayed even after surgical resection until the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases may potentially aid in earlier diagnostic discrimination between the two, as well as informing new directions for treatment. In two recent studies, gain-of-function mutations in PIK3CA, a recognized driver oncogene in many human malignancies, have been newly identified in parathyroid carcinoma. To assess the potential specificity for malignant, as opposed to benign parathyroid disease, of PIK3CA hotspot mutations, we PCR-amplified and Sanger sequenced codons 111, 542/545, and 1047 and the immediate flanking regions in genomic DNA from 391 typical, sporadic parathyroid adenomas. Four parathyroid adenomas (1%) had subclonal, somatic, heterozygous, activating PIK3CA mutations. The rarity of PIK3CA activating mutations in benign parathyroid adenomas suggests that tumorigenic activation of PIK3CA is strongly associated with malignant parathyroid neoplasia. However, it does not appear that such mutations, at least in isolation, can be relied upon for definitive molecular diagnosis of parathyroid carcinoma. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Analysis of Activating GCM2 Sequence Variants in Sporadic Parathyroid Adenomas.

CONTEXT: Sporadic, solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). Apart from germline variants in certain cyclin-dependent kinase inhibitor genes and occasionally in MEN1, CASR, or CDC73, little is known about possible genetic variants in the population that may confer increased risk for development of typical sporadic adenoma. Transcriptionally activating germline variants, especially within in the C-terminal conserved inhibitory domain (CCID) of glial cells missing 2 (GCM2), encoding a transcription factor required for parathyroid gland development, have recently been reported in association with familial and sporadic PHPT. OBJECTIVE: To evaluate the potential role of specific GCM2 activating variants in sporadic parathyroid adenoma. DESIGN AND PATIENTS: Regions encoding hyperparathyroidism-associated, activating GCM2 variants were PCR amplified and sequenced in genomic DNA from 396, otherwise unselected, cases of sporadic parathyroid adenoma. RESULTS: Activating GCM2 CCID variants (p.V382M and p.Y394S) were identified in six of 396 adenomas (1.52%), and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, approximately threefold greater than their frequency in the general population. CONCLUSIONS: The examined, rare CCID variants in GCM2 were enriched in our cohort of patients and appear to confer a moderately increased risk of developing sporadic solitary parathyroid adenoma compared with the general population. However, penetrance of these variants is low, suggesting that the large majority of individuals with such variants will not develop a sporadic parathyroid adenoma.