Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.

Assessing thyroid cancer risk using polygenic risk scores.

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Variants in LRRC34 reveal distinct mechanisms for predisposition to papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (LRRC34). METHODS: We report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis. RESULTS: We observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of LRRC34 containing regulatory variants with allele-specific expression. Transcriptome profiling of LRRC34 knockdown cells showed changes in genes involved with cellular movement. LRRC34 knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis. CONCLUSIONS: Our study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

Hypertrophic cardiomyopathy genetic test reports: A qualitative study of patient understanding of uninformative genetic test results.

Studies have shown that patients with hypertrophic cardiomyopathy (HCM) may misinterpret the meaning of uninformative genetic testing results to mean that a genetic etiology and family members' risk is ruled out. We hypothesized that poor comprehension of the laboratory genetic test report may contribute to this misunderstanding. We conducted a qualitative study to examine patient understanding of uninformative laboratory results and reports and elicit suggestions for an improved report. Fifteen participants with HCM were interviewed after undergoing genetic testing and receiving their report. While all patients read the report, most participants reported only partially reading it. Most reported not understanding the report at all or only partially understanding it because a provider explained it to them. Some participants said that the report was helpful for understanding their result, but there was evidence of misunderstanding; most participants stated that specific aspects of the report were unhelpful. While most of our participants communicated risk with relatives, none said that the report helped with the communication. Most participants did not recall or find the accompanying physician-directed result letter useful for their understanding or familial communication. Many participants expressed need for a supplemental report that illustrates a personalized clinical 'action plan' that could summarize clinical and familial implications of the result for the patient and their family. We conclude that laboratory reports and physician-directed result letters did not help participants understand their results or their familial implications. Our results suggest opportunities for research to explore the utility of a patient-directed result supplement to improve patient comprehension of genetic test results and outline clinical recommendations via a patient action plan.

The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.

PURPOSE: To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus. METHODS: We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets. RESULTS: We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4. CONCLUSION: Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.

Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2.

We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis. The identification of common clinical features in these four individuals along with the characterization of complex segmental duplications flanking the deletion regions suggests that nonallelic homologous recombination mediated these rearrangements and that deletions in 16p11.2-p12.2 constitute a previously undescribed syndrome.

SDHA secondary findings in germline testing: counseling and surveillance considerations.

This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.

Presumed Pathogenic Germ Line and Somatic Variants in African American Thyroid Cancer.

Background: African American (AA) thyroid cancer patients have worse prognoses than European Americans (EA), which has been attributed to both health care disparities and possible genetic differences. We investigated the impact of both germ line and somatic variants on clinical outcome in a cohort of AA nonmedullary thyroid cancer (NMTC) patients who had received therapeutic intervention from cancer centers. Methods: Whole-exome sequencing was performed on DNA from available blood/normal tissues (N = 37) and paired tumor samples (N = 32) collected from 37 and 29 AA NMTC patients, respectively. Variants with Combined Annotation Depletion Dependent (CADD) score of ≥20 and VarSome Clinical classification of likely pathogenic or pathogenic were classified as presumed pathogenic germ line or somatic variants (PPGVs/PPSVs). PPGVs/PPSVs in cancer-related genes and PPGVs in cardiovascular risk genes were further investigated, and PPGVs/PPSVs associated with African (AFR) ancestry were identified. Results: Among 17 PPGVs identified in 16 cancer predisposition or known cancer-related genes, only WRN was previously known to associate with NMTC predisposition. Among PPSVs, BRAFV600E was most the prevalent and detected in 12 of the 29 (41%) tumors. Examining PPGVs/PPSVs among three patients who died from NMTC, one patient who died from papillary thyroid carcinoma/anaplastic thyroid carcinoma (PTC/ATC) led us to speculate that the PPGV ERCC4R799W may have increased the risk of PPSV TP53R273H acquisition. Among PPGVs identified in 18 cardiovascular risk genes, PPGVs in SC5NA, GYG1, CBS, CFTR, and SI are known to have causal and pathogenic implications in cardiovascular disease. Conclusion: In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that health care disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate the acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events, which could be exacerbated by therapy-induced cardiotoxicity, needs to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.

Indolent behavior of malignant Bethesda III nodules compared to Bethesda V/VI nodules.

BACKGROUND: The Bethesda System classifies all fine needle aspiration specimens into one of six categories. We speculated that cancers within each Bethesda category would have distinct clinical behavior. METHODS: This is a retrospective analysis of patients from a single academic medical center with a histologic diagnosis of thyroid cancer who had an initial diagnosis of Bethesda III, IV, V, or VI cytology. RESULTS: A total of 556 cases were included, with 87 cases of Bethesda III, 109 cases of IV, 120 cases of V, and 240 cases of VI. Bethesda III showed similarities with V/VI compared to IV with predominance of papillary thyroid cancer. The interval from diagnosis to surgery was longer in Bethesda III compared to Bethesda V/VI (median 78 vs. 41 days, p<0.001) (Figure 1). Yet, patients with Bethesda III had a higher probability of achieving remission (62 vs.46 %, p<0.03), a lower possibility of recurrence (8 vs. 24%, p<0.001) and a shorter interval to achieve remission (median 1218 vs.1682 days p = 0.02) compared to Bethesda V/VI which did not change after adjusting for age, gender, radioactive iodine therapy, mode of surgery and tumor size. More than 70% of Bethesda III that later presented with recurrence had T3/T4 disease or distant metastasis. CONCLUSIONS: Cancers with Bethesda III cytology had a less aggressive clinical phenotype with better prognosis compared to V/VI despite histological similarities. The time to remission was shorter in Bethesda III despite a longer interval between diagnosis and surgery. The initial cytological diagnosis may guide management.

PDPR Gene Variants Predisposing to Papillary Thyroid Cancer.

Background: Papillary thyroid cancer (PTC) is the predominant subtype of thyroid cancer (THCA), and it can cluster in families with an autosomal dominant (AD) inheritance pattern. The aim of this study was to identify novel genes and mechanisms underlying PTC susceptibility. Methods: Our previous investigation of 17 AD PTC families led us to conduct a deeper analysis on one family (Family Q) with whole-genome sequencing data from 3 PTC-affected individuals. In addition, 323 sporadic THCA cases from Avatar data and 12 familial adenomatous polyposis (FAP) individuals with secondary THCA were screened for pyruvate dehydrogenase phosphatase regulatory (PDPR) variants. CRISPR-Cas9 was used to create PDPR-deficient THCA (TPC1) and transformed normal thyroid cell lines (N-Thyori3-1) to study the metabolic consequences of PDPR loss. Results: We found truncating PDPR splice donor variants (NM_017990.4:c.361 + 1G>C) in all affected PTC Family Q members, and another PDPR splice donor variant (NM_017990.4:c.443 + 1G>C) in a sporadic PTC case. In addition, an ultra-rare missense variant was found in an FAP-PTC patient. The PDPR-deficient cells presented with elevated phosphorylation of pyruvate dehydrogenase and altered glucose metabolism, implying that PDPR plays an essential part in regulating glucose metabolism in thyroid cells. Conclusions: Our finding of novel truncating germline variants in PDPR in Family Q and additional cohorts suggests a role for PDPR loss in PTC predisposition. Also, somatic and RNA sequencing from the thyroid carcinoma (Firehouse Legacy) data showed that PDPR gene expression is much lower in THCA tumor tissue compared with matching normal tissue. Thus, PDPR appears to have a loss of function effect on THCA tumorigenesis.

CHEK2 Founder Variants and Thyroid Cancer Risk.

Background: Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. Methods: The presence of three CHEK2 founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. Results: The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Conclusions: Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.

Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities.

Segmental duplications, which comprise approximately 5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are approximately 2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is approximately 2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.

Neurotransmitter abnormalities and response to supplementation in SPG11.

OBJECTIVE: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin. DESIGN: Case reports. SETTING: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program. PATIENTS: Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy. INTERVENTIONS: L-Dopa/carbidopa and sapropterin. RESULTS: 3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to L-dopa as well as sapropterin. CONCLUSIONS: In the SPG11 patient with extrapyramidal symptoms, a trial of L-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.

Genetic evaluation of patients and families with concern for hereditary endocrine tumor syndromes.

Hereditary endocrine tumor syndromes are rare conditions with overlapping features. It is imperative that healthcare providers differentiate between these syndromes for proper patient care. Advances in genetic testing technologies have increased utilization of genetic counseling and testing in this field; however, few endocrine cancer genetics clinics exist. Two years ago, a genetic counselor (GC) specializing in endocrine cancer genetics was added to the multidisciplinary team of the James Neuroendocrine/Thyroid Clinic at The Ohio State University. Here, we report on this experience. In total, 358 patients were seen. The majority were referred by medical oncology (n = 204; 57%) for a personal history of disease (n = 249; 81%). The most common referral indications were pancreatic neuroendocrine tumors (n = 44; 17%), multiple primary tumors (n = 37; 14%), and pheochromocytoma/paraganglioma (n = 35; 14%). Most patients completed genetic testing after genetic counseling (n = 200; 65%). Targeted gene panel testing was the most common testing ordered (n = 98; 32%). Thirty-one patients (15.5%) had ≥ one likely pathogenic variant (LPV) or pathogenic variant (PV) identified. Approximately 37% (n = 11) did not meet genetic testing guidelines for the gene they tested positive for. The most common genes with LPV/PVs were the SDH genes (n = 8) and MEN1 (n = 7). Referral indications with the highest likelihood of LPV/PVs were paraganglioma, medullary thyroid carcinoma, and multiple primary tumors. We believe this data can provide valuable guidance to healthcare providers who see patients with endocrine neoplasia or who are seeking to establish hereditary endocrine cancer clinics.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients' family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Transcriptome analysis discloses dysregulated genes in normal appearing tumor-adjacent thyroid tissues from patients with papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The molecular characteristics of histologically normal appearing tissue adjacent to the tumor (NAT) from PTC patients are not well characterized. The aim of this study was to characterize the global gene expression profile of NAT and compare it with those of normal and tumor thyroid tissues. We performed total RNA sequencing with fresh frozen thyroid tissues from a cohort of three categories of samples including NAT, normal thyroid (N), and PTC tumor (T). Transcriptome analysis shows that NAT presents a unique gene expression profile, which was not associated with sex or the presence of lymphocytic thyroiditis. Among the differentially expressed genes (DEGs) of NAT vs N, 256 coding genes and 5 noncoding genes have been reported as cancer genes involved in cell proliferation, apoptosis, and/or tumorigenesis. Bioinformatics analysis with Ingenuity Pathway Analysis software revealed that "Cancer, Organismal Injury and Abnormalities, Cellular Response to Therapeutics, and Cellular Movement" were major dysregulated pathways in the NAT tissues. This study provides improved insight into the complexity of gene expression changes in the thyroid glands of patients with PTC.

A novel essential splice site variant in SPTB in a large hereditary spherocytosis family.

BACKGROUND: We studied a large family with 22 individuals affected with autosomal dominant hereditary spherocytosis (HS). METHODS: Genome-wide linkage, whole-genome sequencing (WGS), Sanger sequencing, RT-PCR, and ToPO TA cloning analyses were performed. RESULTS: We revealed a heterozygous G>A transition in the 14q23 locus, at position +1 of the intron 8 donor splice site of the spectrin beta, erythrocytic (SPTB) gene. This splice variant (SPTB c.1064+1G>A) was confirmed by Sanger sequencing and showed complete co-segregation with HS in the family. Further RT-PCR reactions and sequencing analysis indicated that the variant leads to the exclusion of exon 8 and subsequent frameshift in exon 9 and a premature stop codon in SPTB. Translation of the altered allele would lead to a truncation with a loss of all spectrin repeat domains in SPTB protein. CONCLUSION: This variant is novel and has not been found in any databases. We propose that this splice variant explains the spherocytosis phenotype observed in this large family.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Challenges and opportunities in genetic counseling for hereditary endocrine neoplasia syndromes.

The Genetic Counseling Working Group from the 16th International Workshop on Multiple Endocrine Neoplasia (MEN 2019) convened to discuss contemporary challenges and opportunities in the area of genetic counseling for individuals and families affected by hereditary endocrine neoplasia syndromes. As healthcare professionals with multidisciplinary training in human genetics, risk assessment, patient education, psychosocial counseling, and research methodology, genetic counselors bring a unique perspective to working toward addressing these challenges and identifying their subsequent opportunities. This Working Group focused on the following broad areas: (1) genetic counseling resources for endocrine neoplasias, (2) candidate gene discovery, (3) implications of increasingly sensitive and expansive genetic testing technologies for both the germline and the tumors, and (4) situating clinical diagnoses for hereditary endocrine neoplasia syndromes in the context of present-day knowledge.

Co-occurrence of multiple endocrine neoplasia type 4 and spinal neurofibromatosis: a case report.

Multiple Endocrine Neoplasia (MEN) type 4 is a rare genetic condition that results from variants of the CDKN1B gene and predisposes individuals to develop endocrine tumors. Spinal neurofibromatosis (SNF) is an uncommon subtype of neurofibromatosis type 1 (NF1) characterized by bilateral neurofibromas of all spinal roots. Here we report a case of the co-occurrence of these syndromes, which has not yet been described in the literature. A male in his 60s presented with Gleason 5 + 4 localized prostate adenocarcinoma treated with radical prostatectomy. Two years later, he developed liver and bone metastasis consistent with trans-differentiation into small cell carcinoma. He developed hypercalcemia due to primary hyperparathyroidism from a parathyroid adenoma treated surgically. His family history was significant for a first-degree relative with a clinical diagnosis of NF1 and several second-degree relatives with multiple café-au-lait macules. Spine MRI showed multiple bilateral neurofibromas. Germline genetic testing showed a pathogenic variant in the CDKN1B gene, a variant in the NF1 gene, and a normal MEN1 gene. In this rare case of MEN4 and SNF, the patient was asymptomatic for much of his life. In addition to parathyroid adenoma and spinal neurofibromas, he had prostate adenocarcinoma with trans-differentiation into metastatic small cell cancer. Whether this diagnosis was coincidental or related to an emerging phenotype remains to be elucidated.