Genetic Testing in a Patient With Suspected Hyperparathyroidism- Jaw Tumor Syndrome (HPT-JT)

Abstract Introduction: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disorder characterized by parathyroid tumors in association with fibro-osseous jaw tumors, uterine tumors and renal lesions. We present a case of suspected HPT-JT. Clinical Case: A 50-year-old female with suspected HPT-JT was referred for treatment of osteoporosis. Patient was initially diagnosed with osteosarcoma in 1980 at age 10, and underwent resection with leg amputation and chemotherapy. Around 1995, she was found to have primary hyperparathyroidism secondary to a parathyroid adenoma and underwent one gland parathyroidectomy. At age 30, she was then found to have multiple uterine tumors requiring hysterectomy. In 2017, she underwent CT abdomen for suspected appendicitis, which revealed multiple renal cysts and hepatic hemangiomas. In 2019, patient was found to have recurrent parathyroid adenoma and underwent revision parathyroidectomy. Pathology revealed hypercellular parathyroid gland consistent with adenoma. Based on constellation of symptoms, HPT-JS was suspected. Patient was referred to genetic counselor. Detailed family history revealed multiple family members affected by malignancies including melanoma, breast cancer, prostate cancer, liver cancer and two cousins with suspected MEN1. She underwent testing for hereditary hyperparathyroidism and melanoma including CDC73 gene. All genetic testing was surprisingly unrevealing. Discussion: CDC73 gene (also known as HRPT2 gene) is responsible for the pathogenesis of HPT-JT. While HPT-JT itself is a rare condition, 60% of patients affected by it, harbor the HRPT2 gene mutation. About 10–15% of these individuals are affected by parathyroid carcinoma. HRPT2 mutated parathyroid adenomas also seem to have some malignant potential. The autosomal dominant inheritance of HPT-JT makes gene testing important since it has implications for other family members and carries weight in clinical management of genetic carriers. Therefore patients with extensive personal or family history of malignancy should be followed closely. Endocrinologists should have a low threshold to refer such patients for genetic counseling and testing. However genetic testing also has its limitations and can only explain 50–75% of cases of HPT-JT syndrome. Hence, even though our patient has a negative genetic screen, the possibility of HPT-JT is not complete ruled out.

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A novel germline BMPR1A variant (c.72_73delGA) in a Japanese family with hereditary mixed polyposis syndrome

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa059 ◽

2020 ◽

Vol 50 (7) ◽

pp. 826-829

Author(s):

Yosuke Miyahara ◽

Hideyuki Ishida ◽

Koichi Kawabe ◽

Hiroyuki Eto ◽

Toyotaka Kasai ◽

...

Keyword(s):

Genetic Testing ◽

Autosomal Dominant ◽

Hyperplastic Polyps ◽

Autosomal Dominant Disorder ◽

Polyposis Syndrome ◽

Japanese Family ◽

Germline Variant ◽

Juvenile Polyps ◽

Increased Risk ◽

Cancer Syndromes

Abstract Hereditary mixed polyposis syndrome (HMPS) is a rare autosomal dominant disorder characterized by a mixture of typical and/or atypical juvenile polyps, adenomas and hyperplastic polyps, resulting in an increased risk of colorectal cancer. In HMPS, four different germline BMPR1A variants from five unrelated families have been reported. This study is the first to report HMPS within a Japanese family. The proband underwent repeated colonoscopic polypectomies over a 5-year period, since the age of 67. Histological examination of these resected polyps revealed adenomas, juvenile-like polyps and hyperplastic changes. Genetic testing was conducted to identify the causative genes for hereditary gastrointestinal cancer syndromes, including BMPR1A. We detected a germline variant, c.72_73delGA, in BMPR1A. The proband’s elder brother, younger sister and nephew have also undergone repeated colonoscopic polypectomies at other clinics. His sister and nephew underwent genetic testing, and the same BMPR1A variant was identified.

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A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia

American Journal of Hypertension ◽

10.1093/ajh/hpz053 ◽

2019 ◽

Vol 32 (8) ◽

pp. 752-758

Author(s):

Peng Fan ◽

Yu-Mo Zhao ◽

Di Zhang ◽

Ying Liao ◽

Kun-Qi Yang ◽

...

Keyword(s):

Genetic Testing ◽

Frameshift Mutation ◽

Stop Codon ◽

Single Gene ◽

Family Members ◽

Premature Stop Codon ◽

Chinese Family ◽

Autosomal Dominant Disorder ◽

Liddle Syndrome ◽

Genetic Sequencing

Abstract BACKGROUND Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.

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Rates of appropriate genetic testing referral for breast cancer patients treated in a multidisciplinary cancer care setting.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.45 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 45-45 ◽

Cited By ~ 1

Author(s):

Caitlin Laurel Gomez ◽

Nicole Ann Dawson ◽

Robyn Lynn Dvorak ◽

Nova Foster ◽

Anne Hoyt ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Family History ◽

Genetic Counselor ◽

Newly Diagnosed ◽

Breast Cancer Patients ◽

Breast Clinic ◽

Jewish Ancestry ◽

The Impact ◽

Genetics Referral

45 Background: Approximately 5% to 10% of women diagnosed with breast cancer have a genetic predisposition, which can affect management recommendations. The National Comprehensive Cancer Network (NCCN) has established guidelines for genetics referral and testing, however recent publications have indicated low rates of family history documentation and appropriate genetics referral. We sought to assess the impact of standardized family history documentation on rates of appropriate genetics referral in a multidisciplinary breast clinic (MDC) setting. Methods: In advance of MDC consultation, women with newly diagnosed breast cancer complete an intake questionnaire which includes documentation of Ashkenazi Jewish ancestry along with a thorough family history. We retrospectively analyzed family history documentation to inform eligibility for genetic testing and rates of appropriate genetics referral. Results: Between June 2012 and April 2014, 202 women with newly diagnosed, nonmetastatic breast cancer were seen in MDC. We noted 100% compliance with family history documentation. Per NCCN Guidelines, genetic testing was indicated in 52% (106 patients), of which 77% were appropriately referred to a genetic counselor for evaluation. All patients who met criteria based on personal history factors including age ≤ 45, triple-negative disease under age 60, or two or more breast primaries under age 50 were appropriately referred. Patients who were eligible but not referred ranged in age from 46 to 93 and were eligible for testing based on Ashkenzi Jewish ancestry (3 patients) or family history factors including a relative with ovarian cancer (3 patients), ≥2 relatives with breast cancer (5 patients), or a relative with breast cancer < age 50 (7 patients). Conclusions: Compared with recently published national averages, rates of appropriate family history documentation and genetic testing referrals are significantly higher in our MDC setting. However, this analysis has identified significant opportunity for improvement via identification of overlooked referral indications. Initiatives are underway to improve future compliance.

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Piebaldism in a 3-month-old infant: Case report

Medicinski pregled ◽

10.2298/mpns1404109m ◽

2014 ◽

Vol 67 (3-4) ◽

pp. 109-110

Author(s):

Olgica Milankov ◽

Radojica Savic ◽

Anica Radulovic

Keyword(s):

Case Report ◽

Family History ◽

Autosomal Dominant ◽

Male Infant ◽

Congenital Absence ◽

Skin Involvement ◽

Left Forearm ◽

Autosomal Dominant Disorder ◽

And Migration ◽

Infant Case

Introduction. Piebaldism is an autosomal dominant disorder characterized by the congenital absence of melanocytes in the affected areas of skin and hair due to mutations of the KIT protooncogene, which affects the differentiation and migration of melanoblasts. Case report. A 3 ? month old male infant was admitted to hospital due to depigmentation of skin in the area of forehead, trunk and extremities. On admission, he had multiple, irregularly shaped areas of leucoderma present at the forehead, abdomen, lower legs and left forearm. Based on the characteristic skin features and family history, we diagnosed the boy?s leucoderma as piebaldism. Conclusion. Vitiligo differs from piebaldism by the presence of unstable hypopigmented lesions that are acquired later in life. Albinism presents with widespread skin involvement and lacks the characteristic hyperpigmented macules within hypopigmented areas.

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Case report on novel mutation in SPAST gene in Polish family with spastic paraplegia

BMC Neurology ◽

10.1186/s12883-019-1561-6 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Aleksandra Klimkowicz-Mrowiec ◽

Anna Dziubek ◽

Malgorzata Sado ◽

Marek Karpiński ◽

Agnieszka Gorzkowska

Keyword(s):

Case Report ◽

Genetic Testing ◽

Family History ◽

Lower Limb ◽

Hereditary Spastic Paraplegia ◽

Novel Mutation ◽

Family Members ◽

Spastic Paraplegia ◽

Limb Spasticity ◽

Lower Limb Spasticity

Abstract Background Hereditary spastic paraplegia is a large group of degenerative, neurological disorders characterized by progressive lower limb spasticity and weakness. The disease was investigated precisely but still clinicians often make incorrect or late diagnosis. Our aim was to investigate the genetic background and clinical phenotype of spastic paraplegia in large Polish family. Case presentation A 37 years old woman presented with 4-year history of walking difficulties. On neurological examination, she had signs of upper motor lesion in lower extremities. She denied sphincter dysfunction and her cognition was normal. Her family history was positive for individuals with gait problems. The initial diagnosis was familial spastic paraplegia. Genetic testing identified a novel mutation in SPAST gene. All available family members were examined and had genetic testing. The same mutation in SPAST gene was identified in other affected family members. All patients caring the mutation presented with different phenotypes. Conclusion This study presents a family with spastic paraplegia due to a novel mutation c.1390G›T(p.Glu464Term) in SPAST gene. Affected individuals showed a range of phenotypes that varied in their severity. This case report demonstrates, the signs of hereditary spastic paraplegia can be often misdiagnosed with other diseases. Therefore genetic testing should always be considered in patients with lower limb spasticity and positive family history in order to help to establish the correct diagnosis.

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Successful integration of genetic counseling in a comprehensive childhood cancer survivorship clinic.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.5_suppl.230 ◽

2017 ◽

Vol 35 (5_suppl) ◽

pp. 230-230

Author(s):

Shafqat Shah ◽

Gregory John Aune ◽

Lindsey Mette ◽

Natalie Poullard

Keyword(s):

Genetic Counseling ◽

Genetic Testing ◽

Family History ◽

Childhood Cancer ◽

Cancer Survivorship ◽

Chart Review ◽

Genetic Counselor ◽

Pilot Project ◽

Cancer Predisposition ◽

Childhood Cancer Survivorship

230 Background: Awareness of inherited genetic risk and cancer predisposition has markedly increased. Research has shown that germline mutations in known cancer predisposition genes are identified in ~8% of pediatric oncology patients. Patients diagnosed years ago did not meet with a Genetic counselor or undergo genetic testing. The annual comprehensive survivorship visit provides cancer survivors an opportunity to review personal and family history and receive Genetic counseling. Methods: Our group initiated a pilot project in our Childhood Cancer Survivorship clinic (CCSC) to assess the feasibility of introducing survivors to a Certified Genetic Counselor (CGC). Initially, a chart review of annual visits that took place over a 3-month period was performed. A record of documentation of family history and genetic counseling was made. During the pilot period, survivors and their families were given the option to meet with a CGC. The CGC prepared a pedigree and made specific written recommendations regarding the indication, if any, for genetic testing in the patient or family. Anonymous post-counseling surveys were mailed to the families to gauge their satisfaction. Results: Prior to the pilot, 38 survivors were seen for annual visits over a 3 month period. Chart review identified no formal genetic counseling. A note of a family history of cancer was made in 1 patient. During the 3 month implementation period, 50 survivors were seen for annual visits. Thirty-four ( ~70%) accepted the offer to see a CGC. Of the 16 that did not meet with a CGC, 3 had significant medical issues that required attention, 2 had Down syndrome and 2 had previous genetic counseling. The rest declined interest with no specific rationale. Very few (3) surveys were returned. All rated the experience highly. Conclusions: Our experience in a multi-disciplinary CCSC supports the feasibility of delivering CGC services to long-term survivors of cancer. A majority of survivors were interested in meeting with the CGC. Further development of this program will focus on educating survivors about cancer predisposition and increasing access to CGC services.

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Clinical characteristics of men with prostate cancer and evaluation of NCCN prostate cancer guidelines on germline genetic testing outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.252 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 252-252

Author(s):

Samantha Greenberg ◽

Brock O'Neil ◽

Kathleen A. Cooney ◽

Lisa M. Pappas ◽

Jonathan David Tward

Keyword(s):

Prostate Cancer ◽

Genetic Testing ◽

Family History ◽

High Risk ◽

Clinical Characteristics ◽

Genetic Counselor ◽

Clinical Information ◽

Risk Groups ◽

Genetic Test Results ◽

History Of

252 Background: Growing evidence suggests up to 12% of men with metastatic prostate cancer (PC) harbor a pathogenic variant (PV) in genes associated with hereditary cancer risk. Updated NCCN PC guidelines include consideration for germline testing (GT) in men with high risk, very high risk, regional, or metastatic PC. As a result, we expanded our criteria for GT in men with PC to include these groups and men with a strong family history for PC beginning in January 2018. This study reports the clinical characteristics and germline findings before and after this expansion. Methods: Men with PC underwent multi-gene genetic testing (GT) for PVs from June 2016-June 2018 with genetic counselors. Clinical information and germline GT results were analyzed. Results: Of 285 eligible men who met with a genetic counselor, there were 201 evaluable GT results. One PV was excluded for suspicion of clonal hematopoiesis of indeterminate potential. Twenty-seven PVs were identified in 24 men (12.4%). Three men had two PVs identified (1.5%), at least one PV of which was in ATM or BRCA2. The most common PVs were ATM (n = 6, 3.0%), BRCA2 (n = 7, 3.5%), MYH (n = 4, 2.0%), and HOXB13 (n = 4, 2.0%). Rate of PVs were not statistically different across the two timeframes of GT, (2016-17, 14%; 2018, 11.2%; p = 0.60). PVs were not statistically associated with a higher ISUP group (1-3: 10.1%, 4-5: 13.6%; p = 0.49) and were distributed across multiple NCCN risk groups. Almost all men tested reported a family history of cancer, with the most frequent cancers reported including PC (n = 79, 39.3%), breast (n = 55, 27.4%), and colon cancer (n = 23, 11.4%). Family history of PC was not statistically associated with genetic test results (PV: 54%, no PV: 37%; p = 0.11). Conclusions: Expanding germline GT criteria will substantially increase patient volume without significant changes to the PV rate. Higher PC risk defined by ISUP or NCCN was not associated with the rate of PVs. Given this finding, further broadening the criteria for GT in PC may be warranted.

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Journal of Neurology ◽

10.1007/s00415-021-10524-7 ◽

2021 ◽

Author(s):

David Mengel ◽

Andreas Traschütz ◽

Selina Reich ◽

Alejandra Leyva-Gutiérrez ◽

Friedemann Bender ◽

...

Keyword(s):

Early Onset ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Family Members ◽

Start Codon ◽

Mrna Levels ◽

Adult Onset ◽

Loss Of Function ◽

Autosomal Dominant Disorder

Abstract Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

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Hereditary Gingival Fibromatosis with Distinctive Facies

The Journal of Contemporary Dental Practice ◽

10.5005/jp-journals-10024-1248 ◽

2012 ◽

Vol 13 (6) ◽

pp. 892-896 ◽

Cited By ~ 2

Author(s):

Sunkara Shree Ramalinga Prasad ◽

Chitturi Radharani ◽

SV Kiran Kumar ◽

Soumya Sinha

Keyword(s):

Family History ◽

Female Patient ◽

Autosomal Dominant ◽

Chief Complaint ◽

Oral Manifestations ◽

Autosomal Dominant Disorder ◽

Rare Type ◽

Gingival Enlargement ◽

Gingival Fibromatosis ◽

Maxilla And Mandible

ABSTRACT Hereditary gingival enlargement also known as gingivitis or familial elephantiasis is a rare type of gingival enlargement. It appears as an isolated autosomal dominant disorder or maybe associated with other conditions. Oral manifestations may vary from minimal involvement of only tuberosity area and the buccal gingiva around the lower molars to a generalized enlargement inhibiting eruption of the teeth. This paper discusses the case of a 13-year-old female patient with distinctive facial characteristics who presented to the department with a chief complaint of swollen gums since 1 year. She had severe diffuse gingival enlargement of the maxilla and mandible. Diagnosis was made based upon clinical examination and family history. Quadrant wise internal bevel gingivectomy procedure was done for the patient to restore her functional and esthetic needs. How to cite this article Prasad SSR, Radharani C, Sinha S, Kumar SVK. Hereditary Gingival Fibromatosis with Distinctive Facies. J Contemp Dent Pract 2012;13(6):892-896.

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Diagnosis of hereditary hemorrhagic telangiectasia in a pediatric patient admitted with diabetes: the utility of genetic testing

Journal of Clinical Case Reports and Studies ◽

10.31579/2690-8808/066 ◽

2021 ◽

Vol 2 (3) ◽

pp. 01-02

Author(s):

Alvaro E. Galvis ◽

Beatrice Batoczki ◽

Iris S. Pecson ◽

Evan Vidal ◽

Craig T. Nakamura

Keyword(s):

Genetic Testing ◽

Pediatric Patient ◽

Hereditary Hemorrhagic Telangiectasia ◽

Autosomal Dominant ◽

Wide Spectrum ◽

Clinical Manifestations ◽

Autosomal Dominant Disorder ◽

Case Presentation ◽

History Of ◽

Vascular Dysplasia

Background: Hereditary hemorrhagic telangiectasia (HHT) formerly known as Osler-Weber-Rendu syndrome is a rare autosomal dominant disorder characterized by vascular dysplasia and a wide spectrum of clinical manifestations. Case presentation: We report the case of an undiagnosed pediatric patient who presented hypoxemia on clinical exam as the only suggestive feature for the presence of HHT. Conclusions: Although HHT diagnosis is based on the finding of characteristic clinical features genetic testing should also be implemented when a family history of the disease is present to help confirm or refute the diagnosis.

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