scholarly journals SAT-LB302 From Urolithiasis to Genetic Testing: An Unusual Presentation of MEN-4 Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bader Nasser Alamri ◽  
Laura Palma ◽  
Sero Andonian ◽  
William D Foulkes ◽  
Juan Andres Rivera
Keyword(s):  
Prostate Cancer ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Renal Stones ◽  
Her Family ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
History Of ◽  
Plasma Metanephrines ◽  
Work Up

Abstract Background:Germline mutations in the CDKN1B gene are responsible for Multiple Endocrine Neoplasia Type 4 (MEN 4) syndrome (Alrezk et al. 2017). Around 20 cases have been reported to date. Here, we report on a new MEN4 family which possibly extends the phenotypic spectrum attributable to germline mutations in CDKN1B. Clinical Case: A 56-year-old female presented with urolithiasis & was found to have hypercalcemia (serum calcium of 2.76 mmol/l ref. 2.12-2.62 mmol/l). Workup was in keeping with primary hyperparathyroidism (PHPT) (PTH 28.7 pmol/l ref. 1.50-9.30 pmol/l; phosphorus 0.89 mmol/l ref. 0.80-1.45 mmol/l). Sestamibi & US of the neck revealed no clear parathyroid adenoma. Two incidental thyroid nodules were benign on FNA cytology. The patient underwent neck exploration & a single enlarged parathyroid gland was removed. Pathology showed an enlarged hypercellular gland. Her calcium & PTH normalized after surgery but recurrence was documented a year later. Her family history was significant for PHPT in two brothers & a history of kidney stones in a third brother. Multi-gene panel testing (CASR, CDC73, CDKN1B, MEN1, RET, Invitae Corp.) revealed a pathogenic variant (PV) in CDKN1B (c.215delG). The patient underwent a 2 ½ parathyroidectomy with subsequent normalization of her calcium & PTH. Further work-up showed a 4.5mm non-secreting pituitary adenoma. Plasma metanephrines & NE were intermittently elevated. Serum gastrin was also mildly elevated 83 pmol/l (<53 pmol/l). A Ga68-DOTATATE PET scan was negative. Her 23-year-old daughter tested positive for the familial PV. She is asymptomatic & has normal calcium & PTH; pituitary function is normal except for an elevated IGF-1 at 63.9 nmol/l (ref 13.3- 42.6 nmol/l) with borderline growth hormone during OGTT (0.40 ug/l). Her pituitary MRI was normal. One brother with history of prostate cancer, PHPT & partial parathyroidectomy has tested positive for the familial CDKN1B variant. A second brother was also found to carry the familial variant & was clinically asymptomatic.Endocrinological workup has revealed he has PHPT, elevated chromogranin A at 196.2 ng/ml (ref <=82), calcitonin at 25 ng/l (normal <=9 ng/l), IFG1 (35.3 nmol/L ref. 13-21) but normal plasma metanephrines. An MRI of the sella shows an 8mm hypoenhancing lesion. On CT, a retroperitoneal hyperenhancing 4cm mass adjacent to the left ilio-psoas was seen, in keeping with a paraganglioma; additionally, he has a congenital left atrophic kidney & ureter. Two additional brothers; one with history of non-Hodgkin’s lymphoma, PHPT & partial parathyroidectomy & a second brother, also with prostate cancer & recurrent renal stones, have yet to be tested. Conclusions: A new MEN4 family is described here which expands the spectrum of clinical manifestations of this syndrome. Of great interest in our cases is the presence of paraganglioma, urological malformation, & pre-clinical GH/IGF1 elevation.

scholarly journals Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Hikmat Abdel-Razeq
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Healthy Women ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Risk Reducing ◽  
Current Guidelines ◽  
Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

Cardiovascular genetics: the role of genetic testing in diagnosis and management of patients with hypertrophic cardiomyopathy

Heart ◽  
2020 ◽  
pp. heartjnl-2020-316798
Author(s):  
Monica Ahluwalia ◽  
Carolyn Y Ho
Keyword(s):  
At Risk ◽  
Clinical Practice ◽  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Family Management ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

Genetic testing in hypertrophic cardiomyopathy (HCM) is a valuable tool to manage patients and their families. Genetic testing can help inform diagnosis and differentiate HCM from other disorders that also result in increased left ventricular wall thickness, thereby directly impacting treatment. Moreover, genetic testing can definitively identify at-risk relatives and focus family management. Pathogenic variants in sarcomere and sarcomere-related genes have been implicated in causing HCM, and targeted gene panel testing is recommended for patients once a clinical diagnosis has been established. If a pathogenic or likely pathogenic variant is identified in a patient with HCM, predictive genetic testing is recommended for their at-risk relatives to determine who is at risk and to guide longitudinal screening and risk stratification. However, there are important challenges and considerations to implementing genetic testing in clinical practice. Genetic testing results can have psychological and other implications for patients and their families, emphasising the importance of genetic counselling before and after genetic testing. Determining the clinical relevance of genetic testing results is also complex and requires expertise in understanding of human genetic variation and clinical manifestations of the disease. In this review, we discuss the genetics of HCM and how to integrate genetic testing in clinical practice.

scholarly journals Immunoglobulin G4-related sclerosing cholangitis mimicking cholangiocarcinoma: a case report and literature review

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052095921
Author(s):  
Cheng Xu ◽  
Yongmei Han
Keyword(s):  
Sclerosing Cholangitis ◽  
Plasma Cells ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Immunoglobulin G4 ◽  
Igg4 Related Disease ◽  
Serum Igg4 ◽  
History Of ◽  
The Common

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a novel clinical disease that is characterized by elevated serum IgG4 concentrations and tumefaction or tissue infiltrated by IgG4+ plasma cells. The clinical manifestations of IgG4-RD depend on the type of tissues affected. IgG4-related sclerosing cholangitis is a type of IgG4-RD. We report a patient who initially visited a local hospital with a 5-month history of jaundice. He was found to have a mass in the upper part of the common bile duct that mimicked cholangiocarcinoma. He underwent surgery in our hospital and was later diagnosed with IgG4-related sclerosing cholangitis. We administered prednisolone 40 mg once a day for treatment. Taking into account the possible side effects of moderate-dose hormone therapy, we also administered teprenone, potassium chloride, and calcium carbonate. The patient did not have any recurrence of symptoms or adverse drug reactions during follow-up.

Impact of hereditary multigene panel testing for cancer survivors.

2016 ◽  
Vol 34 (3_suppl) ◽  
pp. 261-261
Author(s):  
Nimmi S. Kapoor ◽  
Jennifer Swisher ◽  
Rachel E. McFarland ◽  
Mychael Patrick ◽  
Lisa D. Curcio
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Cancer Survivors ◽  
Gene Mutation ◽  
Gene Panel ◽  
Personal History ◽  
Panel Testing ◽  
Pathogenic Mutations ◽  
Gene Panel Testing ◽  
History Of

261 Background: Recently, genetic testing for hereditary cancer syndromes has seen numerous advances in testing spectrum, capability, and efficiency. This may have important implications for cancer survivors and their families. The purpose of this study is to evaluate the impact of reflex genetic testing with newer multi-gene panels on patients with prior negative BRCA1/2 tests. Methods: Data was collected retrospectively from patients who underwent multi-gene panel testing at one of three sites from a single institution between 8/2013-6/2015. Those with a personal history of breast or ovarian cancer and a prior negative BRCA1/2 test were included. Results: Of 914 patients who underwent multi-gene panel tests, 187 met study inclusion criteria. Ten patients (5.3%) were found to carry 11 pathogenic mutations, including 6 patients with mutations in CHEK2, 2 patients with mutations in PTEN, and 1 patient each with mutations in the following genes: BARD1, NF1, and RAD51C. One patient had two pathogenic mutations identified—CHEK2 and BARD1. Of 10 patients with mutations, 9 had a personal history of breast cancer diagnosed at a median age of 43 (range 35-52) and 1 had ovarian cancer diagnosed at age 65. A majority of mutation carriers underwent panel testing years after their cancer diagnosis (median 6 years, range 0.5-32 years) and none with delayed testing had undergone prophylactic contralateral mastectomy prior to the discovery of their gene mutation. All patients with mutations had a family history of at least one cancer, with most having a variety of cancer diagnoses in multiple relatives. Positive panel testing results altered clinical management in most patients, including addition of breast MRI, colonoscopy, or thyroid ultrasound depending on the gene mutation. After discovery of a PTEN mutation 19 years after her initial cancer treatment, one woman underwent bilateral prophylactic mastectomy and was found to have occult ductal carcinoma in situ. Conclusions: Cancer survivorship must incorporate advances in technology that may be beneficial even years after treatment has ended. Multi-gene panel testing can be applied in survivorship settings as a useful tool to guide screening recommendations.

scholarly journals Xeroderma Pigmentosum with Severe Neurological Manifestations/De Sanctis–Cacchione Syndrome and a Novel XPC Mutation

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Esteban Uribe-Bojanini ◽  
Sara Hernandez-Quiceno ◽  
Alicia María Cock-Rada
Keyword(s):  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Genetic Disorders ◽  
Clinical Manifestations ◽  
Skin Lesions ◽  
Panel Testing ◽  
First Case ◽  
Skin Malignancy ◽  
Increased Risk ◽  
History Of

Several genetic disorders caused by defective nucleotide excision repair that affect the skin and the nervous system have been described, including Xeroderma Pigmentosum (XP), De Sanctis–Cacchione syndrome (DSC), Cockayne syndrome, and Trichothiodystrophy. Cutaneous photosensitivity with an increased risk of skin malignancy is a common feature of these disorders, but clinical manifestations commonly overlap these syndromes. Several genes have been found to be altered in these pathologies, but we lack more genotype-phenotype correlations in order to make an accurate diagnosis. Very few cases of DSC syndrome have been reported in the literature. We present a case of a 12-year-old Colombian male, with multiple skin lesions in sun-exposed areas from the age of 3 months and a history of 15 skin cancers. He also displayed severe neurologic abnormalities (intellectual disability, ataxia, altered speech, and hyperreflexia), short stature, and microcephaly, which are features associated with DSC. Genetic testing revealed a novel germline mutation in the XP-C gene (c.547A>T). This is the first case of an XP-C mutation causing De Sanctis–Cacchione syndrome. Multigene panel testing is becoming more widely available and accessible in the clinical setting and will help rapidly unveil the molecular etiology of these rare genetic disorders.

Gender disparity: Overlooking hereditary prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 85-85
Author(s):  
Lauren Bowling ◽  
Carin Espenschied ◽  
Michelle Jackson ◽  
Bryan Mak ◽  
Holly LaDuca
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitor ◽  
Clinical History ◽  
Germline Mutations ◽  
Gender Disparity ◽  
Multiple Primary Cancers ◽  
Panel Testing ◽  
Multiple Primaries ◽  
Gene Panel Testing ◽  
Management Recommendations

85 Background: Prostate cancer (PC) has been associated with germline mutations in several genes, most often BRCA2. Recently, 11.8% of men with metastatic PC were found to have germline mutations in BRCA and other DNA-repair genes. These mutations are equally inherited by men and women, both have elevated cancer risks, and National Comprehensive Cancer Network (NCCN) testing and management guidelines exist for male and female carriers. Despite this, over 95% of patients who have hereditary cancer multi-gene panel testing (MGPT) are women. We sought to describe detection rate and mutation spectrum of MGPT in men with PC compared to women with breast cancer (BC). Methods: Test results were reviewed for PC patients and female BC patients who had MGPT (Jun 2013 – May 2016) for up to 49 genes. Clinical history was obtained from test request forms. Results: Of 654 PC probands, 100 germline mutations were identified in 93 men (14.2%), significantly more than women with BC (8.6%; 6,215/71,728; p = 2.5e-5). Most mutations in PC patients were in BRCA (40.9%), followed by ATM (20.4%), CHEK2 (15.0%) and Lynch syndrome-associated genes (9.7%). Of the 100 total mutations, 94% were in genes that would impact management recommendations for them and/or their relatives. The median time from PC diagnosis to MGPT was 6 years, compared to 1 year for female BC. Nearly 57% (53/93) of mutation-positive men had multiple primary cancers, 79.2% of which had PC first. Of BRCA positives with multiple primaries (n = 21), over 90% developed PC followed by subsequent cancers, yet testing was not initiated until another cancer developed. Conclusions: In this cohort of men with PC, MGPT identified germline mutations at significantly higher rates than females with BC. Furthermore, 59.1% (55/93) of mutation positive PC probands had BRCA and/or ATM, making them possibly eligible for a PARP-inhibitor clinical trial. Unfortunately, time from PC diagnosis to MGPT was several years longer than women, allowing many to develop subsequent cancers that may have been prevented or detected earlier with knowledge of the germline mutation. Increased awareness among clinicians is needed to identify more male mutation carriers to enable appropriate cancer risk management for themselves and their relatives.

Pathogenic Variants in BRIP1, RAD51C, and RAD51D Identified with Multi-Gene Panel Testing for Hereditary Cancers

2020 ◽  
Author(s):  
Shelly Cummings ◽  
Susana San Roman ◽  
Jennifer Saam ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Cancer Diagnosis ◽  
Fold Increase ◽  
Ovarian Cancer Risk ◽  
Risk Genes ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of

Abstract Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N=631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results: PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years in BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D.Conclusions: These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45-50 in RAD51D PV carriers and possibly, until age 50-55 in BRIP and RAD51C PV carriers.

Multigene hereditary cancer panel testing for patients with pancreatic cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 244-244
Author(s):  
Anna K McGill ◽  
Sheila R Solomon ◽  
Megan L Marshall ◽  
Lisa Susswein ◽  
Corrine Fillman ◽  
...  
Keyword(s):  
Family History ◽  
Hereditary Cancer ◽  
Diagnostic Yield ◽  
Ductal Adenocarcinoma ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Brca1 Brca2 ◽  
Cancer Panel

244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.

scholarly journals Radiographically Occult Latent Radiogenic Osteosarcoma Uncovered on Tc-99m Methylene-diphosphonate Bone Scintigraphy

2013 ◽  
Vol 3 ◽  
pp. 46 ◽  
Author(s):  
Prashant Jolepalem ◽  
Raymond Y. Yeow ◽  
Diane Cosner ◽  
John P. Seitz
Keyword(s):  
Prostate Cancer ◽  
Bone Scan ◽  
Alkaline Phosphatase Level ◽  
Elevated Alkaline Phosphatase ◽  
Additional Information ◽  
Methylene Diphosphonate ◽  
History Of ◽  
Radiation Induced ◽  
Patient’S History ◽  
Work Up

We present a case of a 70-year-old male who was referred for a technetium-99m methylene-diphosphonate bone scan for mild left hip pain and an elevated alkaline phosphatase level of 770 units/L. No additional information was provided and the patient's history was limited due to a language barrier. We were able to ascertain that the patient had a remote history of prostate cancer, which had been treated with radiation. Originally, we felt the bone scan was compatible with Paget's disease; however, further work-up revealed the presence of osteosarcoma, which was potentially radiation-induced.

scholarly journals Status epilepticus and diabetes ketoacidosis: uncommon clinical presentations of acromegaly

2021 ◽  
Vol 2021 ◽  
Author(s):  
Nyasatu G Chamba ◽  
Ahlam A Amour ◽  
Abid M Sadiq ◽  
Tecla R Lyamuya ◽  
Emmanuel V Assey ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Mass Effect ◽  
Prolactin Secretion ◽  
List Type ◽  
Resource Setting ◽  
Clinical Presentations ◽  
History Of ◽  
New Onset

Summary Acromegaly is a rare disease caused by hypersecretion of the growth hormone (GH). Most cases are caused by either pituitary microadenoma or macroadenoma. The GH producing tumors present with clinical manifestations of acromegaly due to excessive GH secretion or symptoms resulting from mass effects of the enlarging tumor. The physical changes are usually slow and, therefore, recognition of the disease is delayed. These adenomas are never malignant but can have significant morbidity and mortality. A subgroup of patients with acromegaly present with severe hyperglycemia resulting in diabetic ketoacidosis (DKA) which requires insulin. Rarely are pituitary tumors responsible for generalized convulsions except when they are too large. We hereby present two cases, the first is that of a 26-year-old female who presented with new onset status epilepticus, DKA with a 1-year history of diabetes mellitus (DM). On examination, she had clinical features of acromegaly. The second case is that of a 34-year-old female who presented with new onset status epilepticus, hyperglycemia with a history of recently diagnosed DM, and features of gigantism. In both cases, their diagnosis was confirmed by elevated serum GH and later by elevated insulin-like growth factor type 1 levels, and CT of the head demonstrating large pituitary macroadenoma. The importance of clinical history and examination, as well as investigations is vital in the recognition of acromegaly. The prognosis of acromegalic patients depends on early clinical recognition and tumor size reduction by either medical or surgical therapy. Learning points Conditions such as status epilepticus and DKA may be clinical presentations in patients presenting with acromegaly. Seizures are rare in people with pituitary adenoma and typically occur when the tumor invades the suprasellar area due to mass effect on the brain. This article shows how best we were able to manage the acromegaly complications in a low resource setting. Hyperprolactinemia in acromegaly may be due to disruption of the normal dopaminergic inhibition of prolactin secretion due to mass effect of the macroadenoma, and around 25% of GH-secreting adenomas co-secrete prolactin.

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