1 Overview of Genetic Syndromes and DisordersPrepared by 2012 LEND Trainees and Dr. Davis For 2014 LEND Fellows

2 Pediatric Genetics Dysmorpholgy Genetic CounselingAcute Metabolic disorders Chronic Metabolic disorders

4 Types of “Morphology” problemsMALFORMATION- Poor formation of tissue Single anomalies Multiple anomalies If multiple anomalies are a pattern-SYNDROME DEFORMATION-Unusual forces on normal tissue DISRUPTION- Breakdown of normal tissue DYSPLASIA- Abnormal organization of cells in tissue

6 Multiple anomalies Involve multiple organsUsually genetic etiology (even if unknown) Pattern or cluster of anomalies—SYNDROME Minor anomalies (no medical or surgical consequence) Ex: clinodactyly, 2-3 syndactyly 20-25% of babies with 3 or more MINOR anomalies have a Major malformation! Major anomalies (cosmetic, medical or surgical consequence) Ex: Cong Heart Disease, Hydrocephalus

7 22q11.2 Deletion Syndrome Jayme Ellerbe

13 Sources Accessed 20 Nov 2012. conditions/22q11.2-deletion-syndrome, Accessed 20 Nov Goldmuntz E. DiGeorge syndrome: new insights. Clin Perinatol. 2005;32(4):963-78, ix-x.

17 Resources for Parents Angelman Syndrome Foundationangleman.org Angelman Syndrome Association angelmansyndrome.org

18 Sources diagnoses-and-conditions/angelman- syndrome/description as/ tml

20 Prader-Willi Syndrome (PWS)

21 Prader-Willi Syndrome (PWS)Name and main features PWS was first described by Swiss doctors Andrea Prader, Alexis Labhart and Heinrich Willi in 1956 based on the clinical characteristics of nine children they examined.  The common characteristics defined in the initial report included: small hands and feet, abnormal growth and body composition (small stature, very low lean body mass and early onset childhood obesity), hypotonia (weak muscles) at birth, insatiable hunger, extreme obesity and intellectual disability.

23 Syndrome is life limiting TABLE 3Syndrome is life limiting TABLE 3. Suggested New Criteria to Prompt DNA Testing for PWS Age at Assessment Features Sufficient to Prompt DNA Testing Birth to 2 y 1. Hypotonia with poor suck. 2y–6 y Hypotonia with history of poor suck. 
 Global developmental delay. 6y–12 y History of hypotonia with poor suck (hypotonia often persists). Excessive eating (hyperphagia; preoccupation with food) with central obesity if uncontrolled. 13 y through adulthood Cognitive disabilities; usually mild ID. Hypothalamic hypogonadism and/or typical behavior problems (including temper tantrums, perseverative and compulsive-like behaviors). Modified from PEDIATRICS (ISSN ) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP Reference:
Meral Gunay-Aygun, Stuart Schwartz, Shauna Heeger, Mary Ann O'Riordan and Suzanne B. Cassidy Pediatrics 2001;108;92-DOI: /peds e92  Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34:917–923 Last edited 02/09/2012 Modified from PEDIATRICS (ISSN ) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP Reference:
Meral Gunay-Aygun, Stuart Schwartz, Shauna Heeger, Mary Ann O'Riordan and Suzanne B. Cassidy Pediatrics 2001;108;92-DOI: /peds e92  Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34:917–923 Last edited 02/09/2012 pwsausa

24 TABLE 2. Sensitivities and the Percentages of Documentation of the Published Criteria 
      Major criteria  Percentage Affected Neonatal hypotonia 88 Feeding problems in infancy 79 Excessive weight gain 67 Facial features Hypogonadism 51 Developmental delay 99 Hyperphagia 84 Modified from PEDIATRICS (ISSN ) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP Reference:
Meral Gunay-Aygun, Stuart Schwartz, Shauna Heeger, Mary Ann O'Riordan and Suzanne B. Cassidy Pediatrics 2001;108;92-DOI: /peds e92  Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34:917–923 Last edited 02/09/2012 pwsausa Modified from PEDIATRICS (ISSN ) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP Reference:
Meral Gunay-Aygun, Stuart Schwartz, Shauna Heeger, Mary Ann O'Riordan and Suzanne B. Cassidy Pediatrics 2001;108;92-DOI: /peds e92  Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34:917–923 Last edited 02/09/2012

25 TABLE 2 (Continues). Sensitivities and the Percentages of Documentation of the Published Criteria 
      Minor criteria  Percentage Affected Decreased fetal activity 62 Behavior problems 87 Sleep disturbance/sleep apnea 76 Short stature 63 Small hands and/or feet 88 Narrow hands/straight ulnar borders  82 Eye abnormalities 68 Thick viscous saliva 89 Articulation defects 80 Skin-picking 83 Modified from PEDIATRICS (ISSN ) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP Reference:
Meral Gunay-Aygun, Stuart Schwartz, Shauna Heeger, Mary Ann O'Riordan and Suzanne B. Cassidy Pediatrics 2001;108;92-DOI: /peds e92  Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34:917–923 Last edited 02/09/2012 Modified from PEDIATRICS (ISSN ) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP Reference:
Meral Gunay-Aygun, Stuart Schwartz, Shauna Heeger, Mary Ann O'Riordan and Suzanne B. Cassidy Pediatrics 2001;108;92-DOI: /peds e92  Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997;34:917–923 Last edited 02/09/2012 pwsausa

26 Sources and Resources http://fpwr.org/about-prader-willi-syndromesyndrome/DS00922/DSECTION=causes and-conditions/prader-willi-syndrome/description

32 Resources for Parents New and Expectant Parents: National Down Syndrome Congress: National Down Syndrome Society: National Association for Down Syndrome:

33 Sources 1. Olson, L. E., Richtsmeier, J. T., Leszl, J., & Reeves, R. H. (2004). A chromosome 21 critical region does not cause specific down syndrome phenotypes. Science, 306(5696), Retrieved from ?accountid=14473 2. Horowitz, K., Incerti, M., Roberson, R., Abebe, D., Toso, L., Caballero, M., Spong, C. Y., (January 2012) Prenatal treatment prevents learning deficit in down syndrome model. American Journal of Obstetrics and Gynecology, 206,(1), S35. 3. World Health Organization (2012), Genomic Resource Center. Down Syndrome. 4. Mayo Clinic Staff (2011) Down syndrome. syndrome/DS00182 5. National Institutes of Health (2012) Medline plus. Down syndrome. U.S. Department of Health and Human Services.

35 Fragile X (FXS) Karrianna Gallagher Caused by a mutation on the FMRI gene of the X chromosome Features vary, but are more apparent in males than females Males Females Intellectual disability (Average IQ of 50) Intellectual disability in 30% Behaviors similar to ASD Learning difficulties Macrocephaly Short attention span Common facial features, such as: long, narrow face, tall forehead, flat nasal bridge, large ears (features are subtle) Common physical features: large ears, flexible finger joints, and flat feet Flexible finger joints and flat fee Moodiness, shyness, anxiety Postpubertal macroorchidism (Kerr, 2008)

37 Resources for Parents General information about Fragile X from Medline Plus For children 0-3 years, contact the Alaska Infant Learning Program for information regarding services such as speech, physical, and occupational therapy LINKS – National Fragile X support network Fraxa Foundation – Promotes Fragile X research

39 Muscular Dystrophy Muscular Dystrophy is a category of conditionsCarrie Plant Muscular Dystrophy is a category of conditions There are more than 30 forms of “MD” All forms of MD have the following in common: Inherited Affects the muscles (muscle weakness/loss) Affects the individual in a unique way Progressive degeneration, loss of skills No “cure” Have a variety of treatment options to help individuals maintain skills and/or adapt to changes in their body

41 Resources for FamiliesMDA: Muscular Dystrophy Association Parent Project Muscular Dystrophy Muscular Dystrophy Family Fund The Diagnosis and Management of Duchenne Muscular Dystrophy: A Guide for Families Fact Sheets and other CDC Resources Fascioscapulohumeral Muscular Dystrophy Society CDC Early Diagnosis Project University of Washington/MDA MD Clinic MDA Alaska

42 More Resources for FamiliesDMD-A Guide for Parents Becker MD DMD Pioneers: Exploring New Horizons Cure CMD: Congenital Muscular Dystrophy Myotonic Dystrophy Foundation Jain Foundation National Registry Facioscapulohumeral Muscular Dystrophy Canada Foundation Muscular Dystrophy Canada Animated Video to Explain MD to Classmates Books about MD and a Family Memoir and More Books

43 Sources PubMed Health (National Institute of Health)Medline Plus (National Institute of Health) Mayo Clinic OrthoInfo (American Academy of Orthopaedic Surgeons) CDC Your Genes Your Health

44 MCADD Medium Chain Acyl CoA Dehydrogenase DeficiencyLynn Palmquist Description and main features: People with this disorder have a difficult time breaking down body fat or fat from food into energy for the body. This is due to enzymes that are not working correctly. Our body first uses glucose for energy. When that is used up, it turns to fat for energy. People with MCADD, cannot use fat for energy and experience low blood sugar- hypoglycemia An inherited metabolic disorder

45 MCADD How common is it? 1:50,000 live births More common in Caucasians from Northwestern Europe ancestry (1:70 Caucasians are carriers) Newborn screenings do not always detect MCADD Symptoms (Some children do not experience symptoms) Usually onset between 3-15 months Extremely sleepy, irritable, poor appetite, fever, diarrhea, vomiting, and hypoglycemia If not treated: Breathing problems, seizures, coma, death Is this condition life limiting? If treated, ideally no. If not detected early may cause death, learning disabilities, intellectual disability, chronic muscle weakness, spasticity, and other effects

47 Resources for Parents CLIMB (Children Living with Inherited Metabolic Diseases) FOD (Fatty Oxidation Disorders) Family Support Group wlfodsupport.org Genetic and Rare Diseases (GARD) Information Center United Mitochondrial Disease Foundation Medium Chain Acyl-CoA Dehydrogenase Deficiency: MCAD A Guide for Parents /PDFs_all /mcad_eng.pdf

48 Sources Genetic fact sheets for parents: Fatty acid oxidation disorders (2011). Screening, technology, and research in genetics. Retrieved from html Longo, N.(updated 2010). MCADD. Medical Home Portal. Retrieved from MCAD (updated 2012). Genetics home reference. Retrieved from dehydrogenase-deficiency Medium chain acyl-CoA dehydrogenase deficiency: MCAD a guide for parents (2005). Western states genetic services collaborative. Retrieved from /mcad_eng.pdf Medium chain acyl CoA dehydrogenase deficiency (2008). National organization for rare disorders, Inc. Retrieved from https://www.caring4cancer.com/go/community/tools/knowledgebase/ Article.aspx?wi d=nord585

53 Phenylketonuria (PKU)Ursula Jones Description and Main Features: recessive disorder caused by deficiency in phenylalanine hydroxylase accumulation is toxic for the development and functioning of the central nervous system and leads to intellectual disability Phenylalanine is present in almost all foods containing proteins Most children with PKU are identified by newborn screening

54 Phenylketonuria (PKU)How common is it? PKU occurs in about 1/10,000 live births in the US1 The incidence varies greatly in other populations: Turks - 1/2,600; Irish - 1/4,500; African - 1/100,000; Japanese - 1/143,000; Finnish and Ashkenazi Jewish - 1/200,0002

55 Phenylketonuria (PKU)Is this condition life limiting? With treatment and early introduction and maintenance of the special diet, normal IQ and development can be expected. Without treatment, symptoms in classic PKU begin by about 6 months of age. If patients remain untreated they may develop: decreased skin and hair pigmentation (due to lack of tyrosine) eczema seizures profound mental retardation Diet restriction needs to be continued for life in patients with PKU and repeated monitoring of plasma phenylalanine and tyrosine levels are needed to make sure that they remain within the therapeutic range (phenylalanine micromolar, Tyrosine micromolar)

56 Resources for Parents and-conditions/phenylketonuria-and-pterin- defects/description#Prevalenced37025e122 H / s_pku.html a ria/DS00514

57 Sources 1 - Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics. 2003;111(6 Pt 1): 2 - Günther T, Schreiber C, Noebauer C, Eicken A, Lange R. Treatment strategies for pediatric patients with primary cardiac and pericardial tumors: a 30-year review. Pediatr Cardiol. 2008;29(6): conditions/phenylketonuria-and-pterin- defects/description#Prevalenced37025e122

61 Rett Syndrome Genetics:RS is due to a mutation of the MECP2 gene on the X chromosome [2,4] However, not all MECP2-related disorder are RS [2,4] 20% of females presenting with RS are negative for a MECP2 mutation [2] Females with RS usually survive since they have two X chromosomes and the mutation is only present on one [1] Males have only 1 X chromosome and the mutation usually results in miscarriage, stillbirth, or very early death [1] Typically considered a non-inherited condition [4] Most cases are spontaneous, however, some women have been found to be asymptomatic carriers and present with no clinical symptoms

63 Rett Syndrome PrognosisWhile developmental regression occurs, it is not considered a degenerative disorder [2] . Survival into adulthood is typical, with accounts of individuals living into their 40’s and 50’s. Compared to the general population individuals with RS have higher rates of: uncontrolled seizures, swallowing problems, arrhythmic heart abnormalities all of which lead to higher rates of unexplained death [1, 2] . Treatment There is no cure [1, 2, 4] . Treatment is focused around management of symptoms from a multidisciplinary approach i.e [4] : Medications to manage seizures, respiration irregularities, spasticity, GERD, constipation, etc. Therapy to address ADL’s, mobility and speech concerns Nutritionists

64 Resources for Parents International Rett Syndrome Foundation The Sarah Varon Foundation for Rett Syndrome Research Rett.com: Information and Inspiration for the Rett Syndrom Community Rett Syndrome Research Trust Teach more, Love more (Flordia based Support and Resource Agency) Family Village – Through the University of Wisconsin, Madison

65 Sources 1. A.D.A.M Medical Encyclopedia. (2010, November 12). Rett Syndrome. Retrieved from PMH / 2. Kerr, M. L. (2009, January). Rett Syndrome – Description. Retrieved from conditions/rett- syndrome/description 3. Kerr, M. L. (2008, August). Rett Syndrome – Initial diagnosis. Retrieved from conditions/rett- syndrome/initial-diagnosis#pearlsAndAlerts 4. National Institute of Neurological Disorders and Stroke, Office of Communications and Public Liaison. (2012, November 6). Rett Syndrome fact sheet (NIH Publication No ). Retrieved from

66 Turner Syndrome Stephanie Johnson Turner Syndrome is a chromosomal condition that only occurs in females as a result of having only one normal X chromosome instead of the usual two sex chromosomes. The second X chromosome is either missing or incomplete. TS physical manifestations such as: short stature, ovarian insufficiency, variable presence of malformations in other organ systems (left-sided cardiac defects, lymphedema, short 4th metacarpals, and genitourinary malformations, such as horseshoe kidney). Diagnosis is confirmed by a blood test which analyzes the chromosomal composition of the individual. Condition 45XO, anueploidy

68 Resources for Parents A Guide for Families-Turner Syndrome Society of the US Turner Syndrome Society Annual Conference Volunteer Support Services: Please contact our office at or or and a volunteer will contact you directly. Turner Syndrome Camp, Camp for year-olds with Turner Syndrome, Ft. Collins, Colorado, July 2004, sponsored by Children’s Hospital, Los Angeles, CA (323) , 31/Turner_syndrome.aspx

69 Sources ces/ts-guide-families-214.pdf s-and-conditions/turner-syndrome/initial- diagnosis