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Velo Cardio Facial Syndrome
Slide 1 ___________________________________ Velo Cardio Facial Syndrome: Recognition and Therapy for a Common Microdeletion Syndrome Lorraine Potocki, M.D., F.A.C.M.G. Professor Department of Molecular and Human Genetics Baylor College of Medicine Texas Children’s Hospital ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 2 Objectives 1. Define genetic/genomic basis. ___________________________________ ___________________________________ 2. Discus historical context. 3. Review clinical presentation. ___________________________________ 4. Outline medical management. 5. Identify resources for families and professionals. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 3 What is Velo Cardio Facial Syndrome? ___________________________________ Microdeletion of chromosome 22q11.2 ___________________________________ Associated with congenital anomalies, endocrine and immunologic abnormalities, cognitive disabilities and psychological disturbances. ___________________________________ Highly variable phenotype. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 4 ___________________________________ …and Widely Variable Nomenclature ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 5 History: What’s in a Name? DiGeorge syndrome Cayler cardiofacial syndrome Takao syndrome Shprintzen syndrome ___________________________________ ___________________________________ ___________________________________ Velo-Cardio-Facial syndrome Sedlacˇkova´ syndrome Conotruncal anomalies face syndrome ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 6 ___________________________________ History ___________________________________ This syndrome was described (based on clinical features) ___________________________________ long before the genetic basis was discovered. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 7 History: What’s in a Name? ___________________________________ ___________________________________ ___________________________________ Angelo DiGeorge, M.D. Pediatric Endocrinologist Robert Shprintzen, Ph.D. Speech Pathologist ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 8 1965 Dr. DiGeorge describes children with low calcium, seizures, infections, and heart defects. ___________________________________ 1976 Dr. Kinouchi reports a typical facial appearance seen in patients with heart problems and calls it conotruncal anomaly facial syndrome (CTAF). 1978 Dr. Shprintzen describes a condition running in families. Patients have cleft palate or velopharyngeal incompetence, heart defects, learning disabilities and a characteristic facial appearance. He calls it velocardiofacial syndrome. 1981/1982 Some patients with DiGeorge syndrome noted to have a rearrangement of chromosome 22 that caused them to be missing a very small piece of chromosomal material on the long arm (q11.2). ___________________________________ ___________________________________ 1990 Some parents of DiGeorge patients noted to have features of VCFS. 1992 DGS and VCFS found to be due to deletion 22q11.2 1994 Diagnostic test (FISH) becomes available in clinical laboratories. ___________________________________ 2004-present Better diagnostic test (Chromosomal DNA “Chip” or Microarray ) is widely used. ___________________________________ ___________________________________ ___________________________________ Slide 9 A single genomic abnormality explains many syndromes ___________________________________ ___________________________________ 22q11.2DS DiGeorge syndrome ___________________________________ Shprintzen syndrome Velo-Cardio-Facial syndrome ___________________________________ Conotruncal anomalies face syndrome ___________________________________ ___________________________________ ___________________________________ Slide 10 ___________________________________ Genetics 101 Chromosomes Ps and Qs Bands Genes ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 11 GENEtics is NOT a 4-letter word ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 12 ~20,000 genes packaged on 23 pairs of chromosomes ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 13 Ideogram Karyotype & FISH ___________________________________ p ___________________________________ q ___________________________________ Deletion 22q11.2 22 Microdeletion is NOT visible on G-banded chromosome analysis . ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 14 Laboratory Diagnosis Karyotype vs FISH vs Microarray ___________________________________ ___________________________________ ___________________________________ Chromosomal microarray (aCGH) is greatly improving the rate of diagnoses. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 15 ___________________________________ Deletion 22q11.2 DiGeorge Velocardiofacial • Presenting in infancy • Childhood/adulthood • Severe heart defects • Minor heart defects • Severe infections • Weak palate; cleft palate • Seizures • Long face and fingers ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 16 ___________________________________ Deletion 22q11.2 Fetal Demise Severe Neonatal Early Childhood School Years Teen Adult ___________________________________ IUFD—CHD/Seizures—Feeding/DD—LDs—Behavior—Psych—Incidental ___________________________________ CATASTROPHIC to ASYMPTOMATIC ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 17 ___________________________________ Deletion 22q11.2 Fetal Demise Severe Neonatal Early Childhood School Years Teen Adult Incidence of ~1 in 2000 Diagnosis is dependent on: Experience and Awareness of Providers Severity of Phenotype ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 18 ___________________________________ Objectives Redefined 1. 2. 3. 4. Recognize 22qDS in your patients. Confirm diagnosis by laboratory testing. Discuss recurrence risk for family members. Provide recommendations for medical intervention and surveillance. 5. Provide information regarding support/advocacy groups. ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 19 Case Presentation ___________________________________ • 10 month old girl • History of atrial septal defect • Developmental delay ___________________________________ ___________________________________ Hypotonia Poor feeding Delayed milestones • Observation in clinic Nasopharyngeal reflux ___________________________________ http://www.smartspeechtherapy.com/spotlight-on-syndromes-an-slps-perspective-on-22q-deletion-syndrome/ ___________________________________ ___________________________________ ___________________________________ Slide 20 What type of Genetic Test would you recommend? • Chromosome analysis NO YEAH YEAH MICROARRAY • FISH for 22q NO • Chromosome microarray ___________________________________ ___________________________________ ___________________________________ ___________________________________ http://www.smartspeechtherapy.com/spotlight-on-syndromes-an-slps-perspective-on-22q-deletion-syndrome/ ___________________________________ ___________________________________ ___________________________________ Slide 21 Intrauterine Fetal Demise 24yo prima gravida; 26yo father No maternal illnesses or exposures Normal ultrasounds Normal maternal serum screens ___________________________________ ___________________________________ Lack of fetal movement at 28 weeks ___________________________________ Consent for autopsy Absent thymus Hypoplastic parathyroid glands Tetralogy of Fallot ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 22 Three Years Later SGA male BTA 27yo G2P1-2 Interrupted aortic arch Hypocalcemic seizures ___________________________________ ___________________________________ ___________________________________ Severe immunodeficiency Overwhelming sepsis ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 23 Diagnostic Approach Chromosomal microarray ___________________________________ ___________________________________ deletion 22q11.2 Should we stop there? family history parental studies mother with deletion 22q ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 24 Recurrence Risk 95% deletions—“de novo” ___________________________________ ___________________________________ ___________________________________ 5% are inherited from a parent. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 25 Recurrence Risk For someone who HAS the deletion Recurrence risk is 50% ___________________________________ ___________________________________ ___________________________________ Always test the parents ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 26 Case Presentation 17yo girl ADHD dx in childhood Learning disabilities identified in H.S. Dx recently with ODD Physical examination CMA revealed 22q11.2 deletion ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 27 Indications for Genetic Evaluation 1. 2. 3. 4. 5. 6. 7. Establish diagnosis Anticipatory guidance Medical management Developmental intervention Behavioral intervention Psychological management Recurrence risk ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 28 Clinical Features of Deletion 22q11.2 ___________________________________ Over 180—involving many organs and systems INTERUPTED AORTIC ARCH HYPERNASAL SPEECH ATTENTION DEFICIT BRAIN GROWTH SPEECH DELAY LOW MUSCLE TONE BIPOLAR DISORDER LEARNING PARATHYROID PALATE SUBMUCOUS CLEFT HEARING LOSS THYMUS HEART DISMOTILITY ANXIETY SEIZURES SCHIZOPHRENIA KIDNEYS VISION INFECTIONS ___________________________________ IMMUNE SYSTEM SWALLOWING PROBLEMS CALCIUM REGULATION GASTROINTESTINAL TRACK GASTROESOPHAGEAL REFLUX ___________________________________ AUTISM NASOPHARYNGEAL REGURGITATION FEEDING DIFFICULTIES ___________________________________ VASCULAR ANOMALIES ___________________________________ ___________________________________ ___________________________________ Slide 29 Diagnosis of Deletion 22q11.2 1 in 2,000 Birth By age 5 years By age 18 years 30% 70% 95% Some people with deletion 22q11.2 are diagnosed Following birth of affected child. ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 30 Clinical Features of Deletion 22q11.2 ___________________________________ Facial features can be very subtle. ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 31 Clinical Features of Deletion 22q11.2 ___________________________________ ___________________________________ No feature occurs in ALL patients. NO patient has all features. ___________________________________ Extremely variable. Current laboratory techniques allow earlier diagnosis. Early diagnosis leads to better clinical and educational outcome ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 32 22q11.2DS: Congenital Anomalies Organ Diagnostic Test Brain EEG; MRI Neurologist **Eye Examination Ophthalmologist **Ear Audiological assessment Audiologist; ENT **Palate Examination; pharynscope ENT; Craniofacial team **Heart Echo; EKG; CXR; MRI chest **Thymus gland Lymphocyte counts/Ig levels Immunology **Parathyroids Ionized calcium levels Endocrinology **Kidney Ultrasound; VCUG Urologist Genitourinary ___________________________________ Follow Up ___________________________________ Cardiology/CV Surgery Testicular ultrasound ___________________________________ Urologist Gastrointestinal Depends on symptoms Gastroenterologist Skeleton X-rays of spine; Chest X ray Orthopedist ___________________________________ **Testing recommended at diagnosis tests in italics may not be necessary ___________________________________ ___________________________________ ___________________________________ Slide 33 22q11.2DS: Anticipatory Guidance Diagnosis Follow Up Heart defects Cardiac surgery; Cardiology Feeding and swallowing difficulties Feeding team; Occupational Rx VPI; Nasal speech Otolaryngology Infections Immunology Hypocalcemia Endocrinology Gastro-esophogeal reflux Gastroenterology Vision; strabismus Ophthalmology Hearing loss Audiology Poor growth (40%) Endocrinology Seizures (10%) Neurology; Endocrinology ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 34 Developmental and Behavioral Problems Diagnosis Follow Up Developmental Delay (70-90%) Early Childhood Intervention Occupational/Physical Therapy ECI; Speech therapy Augmentative communication Developmental specialist Speech delay (70-90%) Articulation difficulty Learning disability (70-90%) Attention deficit Autistic spectrum disorder Schizophrenia; Bipolar Depression; Anxiety disorder Developmental specialist Psychiatrist Developmental specialist Psychiatrist Psychiatrist ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 35 International Consortium on Brain and Behavior in 22q11.2 Deletion syndrome (2014) ADHD—most frequent in children: 37% (M>F) Disruptive disorders—(ODD/Conduct): 7-14% (M>F) Anxiety disorders—↑children and adolescents (F>M) Panic disorder—increased with age Mood disorders—increased with age (F>M) Autism Spectrum—(M=F) ___________________________________ ___________________________________ ___________________________________ ___________________________________ Psychotic disorders—41% of adults >25years ___________________________________ ___________________________________ ___________________________________ Slide 36 ___________________________________ ___________________________________ Survey of 41 caretakers of individuals with deletion 22q11.2. Information about the association between deletion 22q11.2 and psychiatric disease was omitted at diagnosis most of the time and rarely addressed by medical specialists. ___________________________________ Families frequently received their information only from non-medical sources, principally the internet. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 37 Which problems are cause for parental concern? ___________________________________ ___________________________________ ** ___________________________________ Hercher L, Bruenner G. 2008. Living with a child at risk for psychotic illness: The experience of parents coping with 22q11 deletion syndrome: An exploratory study. ___________________________________ Am J Med Genet Part A 146A:2355–2360 . ___________________________________ ___________________________________ ___________________________________ Slide 38 22q11.2 DS Resources Your local geneticist. Internet: GeneReviews www.genetests.org Genetic Home Reference 22q and You (CHOP) VCFS Texas PubMed, Amazon, Google ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 39 References: ___________________________________ Vorstman JA et al (2015): Cognitive decline preceding onset of psychosis in 22q11.2DS. JAMA Psychiatry. Feb [Epub ahead of print] Hidding E et al., (2015): Intellectual function in in relation to autism and ADHD symptomatology in children and adolescents with 22q11.2 DS. J Intellect Disabil Res Feb [Epub ahead of print] Vergaelen E et al., (2015): 3 generation pedigree with paternal transmission of the 22q11.2 DS: intrafamilial phenotypic variability. Eur J Med Genet Feb [Epub ahead of print] Boot E et al. , (2015): Movement disorders and other motor abnormalities in adults with 22q11.2 deletion syndrome. Am J Med Genet. 167:639-645. ___________________________________ Schneider M et al., (2014): Psychiatric disorders from childhood to adulthood in 22q11.2 DS: Results from the International Consortium on Bran and Behavior in 22q11.2 DS. Am J Psychiatry. 171 (6):627-639. Hercher L, Bruenner G. (2008): Living with a child at risk for psychotic illness: The experience of parents coping with 22q11 deletion syndrome: An exploratory study. Am J Med Genet Part A 146A:2355–2360. Shprintzen RJ (2008): Velo-cardio-facial syndrome: 30 years of study. Devel Dis Res Rev 14: 3–10. ___________________________________ Gothelf D et al., (2007): Risk Factors for the Emergence of Psychotic Disorders in Adolescents With 22q11.2 Deletion Syndrome. Am J Psychiatry 164:663–669. 22q and You Website: Children’s Hospital of Philadelphia. http://www.chop.edu/consumer/jsp/division/service.jsp?id=74652 Also see 22q and You Newsletter AND Faces of Sunshine—A Handbook for Parents and Professionals GeneClinics GeneReviews : www.genetests.org PHOTO CREDITS: Images in Pediatric Cardiology www.impaedcard.com/; http://kameronfaile.com/; www.flickr.com/photos; University of Kansas http://www.kumc.edu/; www.biyolojiegitim.yyu.edu.tr/.../velum_jpg ; www.md.ucl.ac.be/peca/images/boy.gif ___________________________________ ___________________________________ ___________________________________ ___________________________________
