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PGD: a Celebration of 20 Years
PGD: A Celebration of 20 years: What is Reality and What is Not? Roma June 30, 2010 Mark Hughes, M.D., Ph.D . Professor of Genetics, Internal Medicine, Pathology Director, Genesis Genetics Institute Director, State of Michigan Genomic Technology Center Reality – (Three obvious ones) PGD • Has led to the birth of thousands of healthy children to very desperate, genetically at-risk couples. • Remains at the very limit of medical diagnostic testing • The technology continues to improve - – but it is not reality to think PGD will ever have a 0% false positive or false negative rate Reality: We still do not know What is best to biopsy, and when? Polar Body Blastomere Trophoectoderm Variation in Biopsy Skill Clinic Biopsies +HCG / ET 1 314 17% 2 427 26% 3 181 12% 4 712 31% Reality: We all are controversial • PGD has raised international controversy – How is it bioethically different from Prenatal Testing? – Who should control the use of these technologies? – Should there be government PGD testing standards? • What is the difference between a Disease and a Trait - and who decides? PGD Disorders (A, B, C) • ACHONDROPLASIA (FGFR) • BARTH DILIATED CARDIOMYOPATHY • ACTIN-NEMALIN MYOPATHY (ACTA) • BETA THALASSEMIA (HBB) • ADRENOLEUKODYSTROPHY (ABCD) • BLOOM SYNDROME • AGAMMAGLOBULINEMIA-BRUTON (TYKNS) • BREAST CANCER (BRCA1 & 2) • ALAGILLE SYNDROME (JAG) • CACH-ATAXIA (EIFB) • ALDOLASE A, FRUCTOSE-BISPHOSPHATE • CADASIL (NOTCH) • ALPHA THALASSEMIA (HBA) • CANAVAN DISEASE (ASPA) • ALPHA-ANTITRYPSIN (AAT) • CARNITINE-ACYLCARN TRANSLOCASE • ALPORT SYNDROME -
The Inherited Metabolic Disorders News
The Inherited Metabolic Disorders News Summer 2011 Volume 8 Issue 2 From the Editor I hope everyone is enjoying their summer thus far! Our 8th annual Metabolic Family Day and 7th annual Low In this Issue Protein Cooking Demonstration were once again a huge success. See the section ”What’s New” on page 9 for a full report of the events, as well as pictures. ♦ From the Editor…1 As always, your suggestions and stories are welcome. Please contact me by email: [email protected] or telephone 519-685-8453 if you wish to contribute to the ♦ From Dr. Chitra Prasad…1 newsletter. I hope everyone has a safe and happy summer! ♦ Personal Stories… 2 Janice Little ♦ Featured This Issue … 4 From Dr Chitra Prasad ♦ Suzanne’s Corner… 6 Dear Friends, ♦ What’s New… 8 Hope you all are having a wonderful summer. We had a great metabolic family workshop with around 198 registrants this year. This was truly phenomenal. Thanks to all the team members and ♦ Research & Presentations … 13 the families in the planning committee for doing such a fantastic job. I was really touched when one of our young metabolic patients told her parents that she would like to attend the ♦ How to Make a Donation… 14 metabolic family workshop! Please see some of the highlights of the metabolic workshop in the newsletter for those who could not make it. The speeches by our youth (Sadiq, Leanna and Laura) ♦ Contact Information … 15 were appreciated by everyone. Big thanks to Jill Tosswill (our previous social worker) who coordinated their talks. -
Inherited Bone Marrow Failure Syndrome (IBMFS) Testing
Lab Management Guidelines V2.0.2021 Inherited Bone Marrow Failure Syndrome (IBMFS) Testing MOL.TS.360.A v2.0.2021 Introduction Inherited bone marrow failure syndrome (IBMFS) genetic testing is addressed by this guideline. Procedures addressed The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements. Procedures addressed by this Procedure codes guideline IBMFS Multigene panel 81479 What are inherited bone marrow failure syndromes Definition Bone marrow failure (BMF) is the inability of the bone marrow to produce a sufficient quantity of functional blood cells to meet physiologic demands.1 BMF is typically classified into three categories, based on presumed etiology: inherited, secondary, or idiopathic.1 Inherited bone marrow failure syndromes (IBMFSs) are a group of genetically defined disorders that are characterized by BMF. Individuals presenting with aplastic anemia (AA), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic unexplained cytopenias should be evaluated for an IBMFS.1 Incidence "The incidence of inherited bone marrow failures accounts for 10% to 15% of marrow aplasia and 30% of pediatric bone marrow failure disorders with approximately 65 cases per million live births every year."2 Seventy-five percent of children with an IBMFS have an identifiable cause.2 ©2021 eviCore healthcare. All Rights Reserved. 1 of 17 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V2.0.2021 Symptoms While specific features may vary by each type of IBMFS, features that are present in most IBMFSs include bone marrow failure with single or multi-lineage cytopenia. -
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CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders. -
Associated Palmoplantar Keratoderma
DR ABIGAIL ZIEMAN (Orcid ID : 0000-0001-8236-207X) Article type : Review Article Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: New insight into skin epithelial homeostasis and avenues for treatment Authors: A. G. Zieman1 and P. A. Coulombe1,2 # Affiliations: 1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; 2Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA #Corresponding author: Pierre A. Coulombe, PhD, 3071 Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Tel: 734-615-7509. Email: [email protected]. Funding Sources: These studies were supported by grant AR044232 issued to P.A.C. from the National Institute of Arthritis, Musculoskeletal and Skin Disease (NIAMS). A.G.Z. received support from grant T32 CA009110 from the National Cancer Institute. Author Manuscript This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/BJD.18033 This article is protected by copyright. All rights reserved Conflict of interest disclosures: None declared. Bulleted statements: What’s already known about this topic? Pachyonychia congenita is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts, and oral leukokeratosis. -
EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies
Focusing on Personalised Medicine EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies Extended carrier screening is an important tool for prospective parents to help them determine their risk of having a child affected with a heritable disease. In many cases, parents aren’t aware they are carriers and have no family history due to the rarity of some diseases in the general population. What is covered by the screening? Genomics For Life offers a comprehensive Extended Carrier Screening test, providing prospective parents with the information they require when planning their pregnancy. Extended Carrier Screening has been shown to detect carriers who would not have been considered candidates for traditional risk- based screening. With a simple mouth swab collection, we are able to test for over 419 genes associated with inherited diseases, including Fragile X Syndrome, Cystic Fibrosis and Spinal Muscular Atrophy. The assay has been developed in conjunction with clinical molecular geneticists, and includes genes listed in the NIH Genetic Test Registry. For a list of genes and disorders covered, please see the reverse of this brochure. If your gene of interest is not covered on our Extended Carrier Screening panel, please contact our friendly team to assist you in finding a gene test panel that suits your needs. Why have Extended Carrier Screening? Extended Carrier Screening prior to pregnancy enables couples to learn about their reproductive risk and consider a complete range of reproductive options, including whether or not to become pregnant, whether to use advanced reproductive technologies, such as preimplantation genetic diagnosis, or to use donor gametes. -
PTEN Mutations the PTEN Hamartoma Tumor Synd
Updated December 2019 (NCCN v1.2020) Cowden Syndrome/PTEN Hamartoma Tumor Syndrome: PTEN Mutations The PTEN Hamartoma Tumor Syndrome (PHTS) is a spectrum of highly variable conditions with overlapping features. This spectrum includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and PTEN-related autism spectrum disorder.1-3 The term PHTS describes any individual with a germline pathogenic PTEN mutation, regardless of their clinical presentation.4 PHTS is a multisystem syndrome primarily characterized by noncancerous (benign), tumor-like growths called hamartomas that can develop throughout the body. There is also an increased risk of adult-onset cancers.5 Cancer Risks and General Management Recommendations PTEN Mutation General Surveillance/Management Recommendations9 Carrier Cancer Population Risks2,4-8 Lifetime Cancer Risks Female Breast: 12.4% Surveillance Primary: 33-60% Breast awareness, including periodic, consistent breast self exams, Second Primary: starting at age 18 years 29% within 10 Clinical breast exam every 6-12 months starting at age 25 years, or 5- years10 10 years before the earliest breast cancer diagnosis in the family (whichever comes first) Annual mammogram with consideration of tomosynthesis and breast MRI with contrast at age 30-35 years, or 5-10 years before the earliest breast cancer diagnosis in the family (whichever comes first) Age >75 years: Management should be considered on an individual basis Surgery Discuss option of risk-reducing mastectomy, including degree of protection, reconstruction -
Menkes Disease in 5 Siblings
Cu(e) the balancing act: Copper homeostasis explored in 5 siblings Poster with variable clinical course 595 Sonia A Varghese MD MPH MBA and Yael Shiloh-Malawsky MD Objective Methods Case Presentation Discussion v Present a unique variation of v Review literature describing v The graph below depicts the phenotypic spectrum seen in the 5 brothers v ATP7A mutations produce a clinical spectrum phenotype and course in siblings copper transport disorders v Mom is a known carrier of ATP7A mutation v Siblings 1, 2, and 5 follow a more classic with Menkes Disease (MD) v Apply findings to our case of five v There is limited information on the siblings who were not seen at UNC Menke’s course, while siblings 3 and 4 exhibit affected siblings v The 6th sibling is the youngest and is a healthy female infant (not included here) a phenotypic variation Sibling: v This variation is suggestive of a milder form of Background Treatment birth Presentation Exam Diagnostic testing Outcomes Copper Histidine Menkes such as occipital horn syndrome with v Mutations in ATP7A: copper deficiency order D: 16mos residual copper transport function (Menkes disease) O/AD: 1 Infancy/12mos N/A N/A No Brain v Siblings 3 and 4 had improvement with copper v Mutations in ATP7B: copper overload FTT, Seizures, DD hemorrhage supplementation, however declined when off (Wilson disease) O/AD: Infancy/NA D: 13mos supplementation -suggesting residual ATP7A v The amount of residual functioning 2 N/A N/A No FTT, FTT copper transport function copper transport influences disease Meningitis -
Inherited Metabolic Disease
Inherited metabolic disease Dr Neil W Hopper SRH Areas for discussion • Introduction to IEMs • Presentation • Initial treatment and investigation of IEMs • Hypoglycaemia • Hyperammonaemia • Other presentations • Management of intercurrent illness • Chronic management Inherited Metabolic Diseases • Result from a block to an essential pathway in the body's metabolism. • Huge number of conditions • All rare – very rare (except for one – 1:500) • Presentation can be non-specific so index of suspicion important • Mostly AR inheritance – ask about consanguinity Incidence (W. Midlands) • Amino acid disorders (excluding phenylketonuria) — 18.7 per 100,000 • Phenylketonuria — 8.1 per 100,000 • Organic acidemias — 12.6 per 100,000 • Urea cycle diseases — 4.5 per 100,000 • Glycogen storage diseases — 6.8 per 100,000 • Lysosomal storage diseases — 19.3 per 100,000 • Peroxisomal disorders — 7.4 per 100,000 • Mitochondrial diseases — 20.3 per 100,000 Pathophysiological classification • Disorders that result in toxic accumulation – Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) – Disorders of carbohydrate intolerance – Lysosomal storage disorders • Disorders of energy production, utilization – Fatty acid oxidation defects – Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) – Mitochondrial disorders – Peroxisomal disorders IMD presentations • ? IMD presentations • Screening – MCAD, PKU • Progressive unexplained neonatal -
Amino Acid Disorders 105
AMINO ACID DISORDERS 105 Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical tions in biological fluids relatively easy. These Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663– analyzers separate amino acids either by ion-ex- 667. Churchill Livingstone, New York. Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸a˜o change chromatography or by high-pressure liquid de corantes tri-fenil-metaˆnicos sobre o Trypanosoma cruzi in chromatography. The results are plotted as a graph vitro: Emprego da violeta de genciana na profilaxia da (Fig. 1). The concentration of each amino acid can transmissa˜o da mole´stia de chagas por transfusa˜o de sangue. then be calculated from the size of the corresponding O Hospital (Rio de Janeiro) 44, 731–744. peak on the graph. Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al. (1999). Cerebral tumor-like American trypanosomiasis in Most amino acid disorders can be diagnosed by acquired immunodeficiency syndrome. Ann. Neurol. 45, measuring the concentrations of amino acids in 403–406. blood plasma; however, some disorders of amino Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸ade acid transport are more easily recognized through the Chagas. In Doenc¸as Infecciosas e Parasita´rias (R. Veroesi, Ed.), analysis of urine amino acids. Therefore, screening 7th ed., pp. 674–712. Guanabara Koogan, Sa˜o Paulo, Brazil. Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988). for amino acid disorders is best done using both South American trypanosomiasis (Chagas’ disease). In blood and urine specimens. Occasionally, analysis of Handbook of Clinical Neurology (P. -
To View the ESE Recommended Curriculum of Specialisation in Clinical Endocrinology, Diabetes and Metabolism
European Society of Endocrinology Recommended Curriculum of Specialisation in Clinical Endocrinology, Diabetes and Metabolism Version 2, November 2019 Contents Endorsement ........................................................................................................................................ 2 Introduction .......................................................................................................................................... 3 1. Diabetes mellitus .............................................................................................................................. 4 2. Lipid disorders ................................................................................................................................... 5 3. Obesity and bariatric endocrinology ................................................................................................. 5 4. Pituitary ............................................................................................................................................ 5 5. Thyroid .............................................................................................................................................. 6 6. Parathyroid, calcium and bone ......................................................................................................... 7 7. Adrenal ............................................................................................................................................. 8 8. Reproductive endocrinology and sexual function -
Marfan Syndrome
Marfan syndrome Description Marfan syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, blood vessels, and heart valves. The signs and symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of progression. Because connective tissue is found throughout the body, Marfan syndrome can affect many systems, often causing abnormalities in the heart, blood vessels, eyes, bones, and joints. The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and defects in the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening. Many people with Marfan syndrome have additional heart problems including a leak in the valve that connects two of the four chambers of the heart (mitral valve prolapse) or the valve that regulates blood flow from the heart into the aorta (aortic valve regurgitation). Leaks in these valves can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations). Individuals with Marfan syndrome are usually tall and slender, have elongated fingers and toes (arachnodactyly), loose joints, and have an arm span that exceeds their body height.