Genetics and Dysmorphology

1. Genetics and Dysmorphology Ramanpreet Dhindsa Pediatric Residency Program MCCG

2. Definitions Malformation: Morphologic defect of an organ, part of an organ, or a larger region, resulting from an intrinsically abnormal development process Deformation: Abnormal form or position of a part of the body caused by non disruptive mechanical forces on normally formed tissues Disruption: Structural defect of an organ, part of an organ, or larger region, resulting from a breakdown of or interference with an originally normal development process Dysplasia: Structural defect due to abnormal organization of cells into tissues

3. Contd. Syndrome: A pattern of multiple abnormalities thought to be pathogenically related and not known to represent a sequence Sequence: A pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor Association: The nonrandom occurrence in two or more individuals of multiple idiopathic anomalies of blastogenesis

4. The Genetic Approach in Pediatric Medicine Genetics: Word came from ancient Greek Genesis= Origin The most obvious and severe diseases begin in childhood Major categories of genetic disorders include Chromosomal-Trisomies, Deletions, Duplications, Sex Chromosome Aneuploidy Gene Mutation-Autosomal Dominant, Recessive, X-linked Disorders Multifactorial conditions- Cleft lip, Spina bifida

5. Inheritance Inheritance Patterns Translocations-Reciprocal and Robertsonian Mendelian- Autosomal Dominant, Autosomal Recessive, and X-linked Imprinting Triplet repeat disorders Mitochondrial disorders Multifactorial Traits

6. Specific Disorders Major categories of genetic disorders include Chromosomal-Trisomies, Deletions, Duplications/Insertions, Sex Chromosome Aneuploidy Gene Mutation-Autosomal Dominant, Recessive, X-linked Disorders Multifactorial conditions- Cleft lip, Spina bifida

7. Normal Karyotype

8. Question?? A three year old girl presents for evaluation of recurrent pneumonia (5 times in 2 years) and chronic diarrhea. She is at the 5th percentile for height and weight, What are your differential diagnosis? How would you evaluate this patient?

9. What is this?

10. Genetics�Cystic Fibrosis Mutation in Chr 7 CFTR Over 1200 mutations Most Common Fatal Autosomal Recessive disease in Caucasians 1:2000-3000 About 1:10,000 in Hispanics About 1:50,000 in African Americans

11. Cystic Fibrosis Pulmonary Bronchiolitis/asthma Pseudomonas aeruginosa Digital clubbing Sinusitis GI Meconium Ileus Rectal Prolapse Pancreatic Insufficiency Vitamin deficiency states (A, D, E, K) Volvulus in fetal life Faiure to Thrive GU Infertility Absence of Vas Deferens

12. Cystic Fibrosis Diagnosis Sweat Chloride Test (Gold Std)- Pilocarpine is applied to the skin to stimulate sweat production and then chloride content of the sweat is measured. A positive result is Cl>60mEq/L. Testing for CFTR gene mutations

13. Question?? A newborn infant has prominent epicanthal folds, small ears, hypotonia, short, broad hands and feet brachycephaly and a heart murmur. The mother notes the baby looks different than her two previous children. How would you evaluate this infant and counsel the mother?

14. What is this?

15. Trisomy 21�Down Syndrome Most Common Chromosomal Abnormality 1:1000 Paternal Age Maternal Age 1/625 at 33 1/30 at 45 94% Trisomy 21 4% Robertsonian Translocation 1-2% Trisomy 21 Mosaicism

16. Trisomy 21�Down Syndrome Atrioventricular septal defect (Endocardial Cushion Defect) VSD Secundum ASD PDA Tetralogy of Fallot

17. Trisomy 21�Down Syndrome Duodenal Atresia Mental Retardation Acute Lymphoblastic Leukemia Thyroid (hypo) Diabetes Immune Deficency Early Alzheimer Dz Atlantoaxial instability

18. What is this?

19. Trisomy 13 Head and Face- Scalp defects, Microphthalmia, Cleft lip and palate (60-80%), microcephaly Chest- Congenital Heart Disease 80% (VSD, PDA, and ASD) Extremites-Overlapping fingers and toes, polydactyly General- Severe developmental delay and growth retardation, only 5% live longer than 6 months.

20. What is this?

21. Trisomy 18 Head and Face-Narrow nose, Prominent occiput, micrognathia, microcephaly, cleft lip and palate Chest- Congenital Heart Disease, Short Sternum, Small nipples, Extremities- Limited hip abduction, overlapping fingers, rocker bottom feet. General-Severe developmental delay and growth retardation. Only 5% live beyond 1 year.

22. Question?? The parents of two year old boy will developmental delay report a history of mental retardation in several male members of their family. What are your differential diagnosis and what diagnostic screening will you recommend?

23. What is this?

24. Klinefelter Syndrome (47, XXY) 1:1000 Rarely diagnosed before puberty Most Common Congenital Abnormality causing Primary Hypogonadism

25. Klinefelter Syndrome (47, XXY) Microtestes <2cm Infertile Tall & Thin Mild Mental Retardation

26. Question?? A sixteen year old girl presents with primary amenorrhea. She has been doing well at school but is not athletic and her height is less than 5 percentile for age. On physical examination she has redundant neck skin, broadly spaced nipples and is Tanner stage 1. How would you evaluate and counsel her?

27. What is this?

28. Turner Syndrome (45, X) 1:2000 to 1:5000 Female births Most Common Chromosomal Abnormality in Females Only 1:1000 45, X survive to term

29. Turner Syndrome (45, X) Lack Secondary Sex Characteristics Streak Ovaries 10 Amenorrhea Coarctation of Aorta Newborn--Lymphedema hands & feet Horseshoe Kidney Common cause Short Stature and Amenorrhea

30. Contd�

31. Turner vs Noonan Turner Females Chromosome d/o (45,X) Near-Nml Intelligence Cardiac�Coarc Amenorrhea & Sterility Noonan Male and Female Nml Karyotype Autosomal Dominant (chr 9) Mental deficiency Cardiac�Pulm stenosis Nml menstral cycle

32. Turner vs Noonan

33. Question?? A mother of an newborn tells you she has taken seizure medications throughout her pregnancy and wants to know what effect this may have on her baby? How would you counsel the mother?

34. Contd. There are a number of important issues to be addressed by the physician when a woman with epilepsy becomes pregnant; these include:� Are antiepileptic drugs necessary? What effect do antiepileptic drugs have on the fetus? What effect does maternal epilepsy have on the fetus? What effect does pregnancy have on seizures? How should the patient be managed during pregnancy and delivery? How should the patient be managed during the postpartum period?

35. Contd. Fetal and neonatal effects � There is an increased risk of both major and minor malformations in fetuses exposed to any of the four major antiepileptic drugs (AEDs): phenytoin, carbamazepine, valproic acid (VPA), and phenobarbital. The term fetal anticonvulsant syndrome is often used to describe infants exposed to AEDs in utero who are born with congenital malformations, however, none of these malformations is specific to AED exposure. Phenytoin � Orofacial clefts, cardiac malformations, and genitourinary defects are the major anomalies described with phenytoin In utero exposure to phenytoin has been associated with the development of neuroblastoma. Phenobarbital � Malformations of the heart, orofacial, and urogenital structures occur with increased frequency with phenobarbital.

36. Contd. Carbamazepine � Carbamazepine has been associated with major malformations and spina bifida. utero to carbamazepine have spina bifida aperta. Valproate in utero develop neural-tube like defects (spina bifida aperta, open lumbosacral myelocele). There also may be a pattern of major malformations consisting of meningomyelocele, cardiovascular, and urogenital malformations with minor craniofacial, skeletal, and genital anomalies. Higher valproate doses were associated with more severe dysmorphia.

37. Question?? You are asked to evaluate a baby in the nursery who is small for gestational age and microcephalic. How would you evaluate the infant? What questions would be important to ask the mother?

38. Contd 1. These five infections are: � Toxoplasmosis Other (syphilis) Rubella Cytomegalovirus (CMV) Herpes simplex virus (HSV)

39. Contd 2. CONGENITAL TOXOPLASMOSIS � Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. Primary infection during pregnancy can result in congenital disease. Most infants with congenital toxoplasmosis are asymptomatic. Although subclinical disease is the hepatosplenomegaly, microcephaly, seizures, jaundice, thrombocytopenia, and, rarely, generalized lymphadenopathy. The classic triad of congenital toxoplasmosis consists of chorioretinitis, hydrocephalus, and intracranial calcifications. Infants with subclinical congenital toxoplasmosis who do not receive treatment have an increased risk of long-term sequelae. The most common late finding is Chorioretinitis which can result in vision loss. Intellectual disability (mental retardation), deafness, seizures, and spasticity also can be seen in a minority of untreated children.

40. Contd 3. CONGENITAL SYPHILIS � Congenital syphilis occurs when the spirochete Treponema pallidum is transmitted from a pregnant woman to her fetus. Infection can result in stillbirth, hydrops fetalis, or prematurity and associated long-term morbidity. Because of this morbidity, great emphasis has been placed on routine syphilis screening of all pregnant women. Most neonates with congenital syphilis are asymptomatic at birth. Overt infection can manifest in the fetus, the newborn, or later in childhood. CONGENITAL RUBELLA � Manifestations of congenital rubella infection (CRI) during the neonatal period may include: Intrauterine growth retardation, Meningoencephalitis, large anterior fontanelle, Hearing loss, Cloudy cornea, cataract, infantile glaucoma, retinopathy, Interstitial pneumonia Cardiac defects, Hepatosplenomegaly, jaundice, hepatitis, diarrhea, Radiolucent bone lesions (in the long bones), Petechiae and purpura ("blueberry muffin lesions"), Adenopathy, Hemolytic anemia, thrombocytopenia

41. Contd 4. Late manifestations � Delayed manifestations of congenital rubella infection (CRI) occur in at least 20 percent of children with symptomatic congenital rubella infection. Some of the late manifestations may relate to subtle damage that is present but not detected in early life. Late manifestations include: Hearing loss Endocrine disorders:include diabetes, thyroid disease, and growth hormone deficiency Eye problemsinclude pigmentary retinopathy cataracts, glaucoma, keratic precipitates, keratoconus, corneal hydrops, microphthalmos, strabismus, and absorption of the cataractous lens Vascular effects: include fibromuscular proliferation of the intima, sclerosis of arteries, systemic hypertension secondary to renal disease, and subretinal neovascularization Progressive panencephalitis Immune defects: Include defects in specific antibody production,repeated infections, and defective T-cell response with associated autoimmune phenomena

42. Question?? The pregnant mother of one of your patients calls to say that prenatal ultrasound revealed that her fetus might have spina bifida. She has not taken multivitamin prior to conception. She wants to know the implications of the disease. How would you counsel her? Should any special precautions be taken at the time of delivery and in the neonatal period?

43. Contd. Myelomeningocele is characterized by a cleft in the vertebral column, with a corresponding defect in the skin so that the meninges and spinal cord are exposed. Spinal dysraphism or spina bifida aperta: neural tissue is exposed Occult spinal dysraphism, is characterized by a cleft in the vertebral column, without a corresponding epithelial defect, and neural tissue is not exposed. There are many different forms of occult spinal dysraphism, ranging from asymptomatic vertebral anomalies, to clinically significant defects in the spinal cord and related structures. If a prenatal diagnosis of myelomeningocele has been made, delivery should occur at a hospital with personnel experienced in the neonatal management of these infants. Delivery before term may be indicated if rapidly increasing ventriculomegaly is observed, provided that fetal lung maturity has been documented. Otherwise, term delivery is preferable. Immediately after birth, the lesion should be briefly assessed to note its location, size, and whether it is leaking CSF . Sterile nonlatex gloves should be used .The defect should be covered with a sterile saline-soaked dressing . Large defects should also be covered by plastic wrap to prevent heat loss. Only the neurosurgeon should remove the dressing. The infant should be placed in a prone or lateral position to avoid pressure on the lesion.

44. Spina bifida

45. Contd. A thorough neurologic examination should be performed. This should include: Observation of spontaneous activity Extent of muscle weakness and paralysis Response to sensation Antibiotics � Prophylaxis with broad spectrum antibiotics should be given until the back is closed to reduce the risk of infection of the central nervous system (CNS). With this precaution and appropriate wound care, early CNS infection is rare Surgical closure � The back lesion should be surgically closed within the first 72 hours after birth; this step further decreases the risk of CNS infection.

46. What is this?

47. Deletions The most common deletions include 1p-,4p-, 5p-, 9p-, 11p-, 13p-, 18p-, 21q- Best known deletion is at 5p-, Cri du Chat Characteristic cry, hypotonia, microcephaly, moonlike face, hypertelorism, high and flat nasal bridge, high arched palate and mental retardation. Prognosis- 10% mortality in first year of life then a normal life span.

48. What do all these children have in common?

49. Common?

50. Contd.

51. Contd�

52. Contd�

53. Microdeletions! Williams Syndrome- Chromosome 7- Round face with full checks, strabismus, supravalvular aortic stenosis, friendly personality, varying degrees of mental retardation Alagille Syndrome- Chromosome 20- Bile duct paucity with cholestatis, pulmonary artery stenosis, ocular abnormalities, butterfly vertebrae, long nose with broad mid nose. Velocardiofacial-Digeorge Syndrome- CATCH 22-conotruncal anomalies (tertrology of fallot), hypoplasia or agenesis of the thymus and parathyroid gland resulting in frequent infections and hypocalcemia, hypoplasia of the auricle and external auditory canal,, cleft palate, short stature, behavior problems.

54. Genomic Imprinting Two copies of most genes are functionally equivalent but in a small number only one the pair is transcribed. Therefore, the active gene will be inherited from a specific parent , and the other copy is silenced by methylation- this is Genomic imprinting

55. Genomic Imprinting Chromosome 15

56. Angelman Syndrome Angelman Syndrome Maternal deletion uncontrollable spontaneous laughter, jerky movements, other motor and mental symptoms

57. Prader- Willi Syndrome Prader-Willi syndrome Paternal deletion: Mental retardation, obesity, short stature, unusually small hands and feet

58. What disease do these two boys have?

59. Insertion- Fragile X Most common inherited cause of mental retardation FMR-1 gene on X Chr Elongation of CGG repeats Premutation 50-200 repeats >200 are affected individuals 50% of carrier females have some developmental delay

60. Fragile X Males Prepubertal Elongated Face Flattened Nasal Bridge Protruding Ears Postpubertal Macroorchidism

61. Next Grouping of Specific Disorders. Major categories of genetic disorders include Chromosomal-Trisomies, Deletions, Duplications, Sex Chromosome Aneuploidy Gene Mutation-Autosomal Dominant, Recessive, X-linked Disorders Multifactorial conditions- Cleft lip, Spina bifida

62. What is this?

63. Marfans Syndrome Marfan Syndrome Autosomal Dominant�Fibrillin Gene 25-30% Sporadic Skeletal Cardiac- aortic dilatation, mitral valve prolapse Ocular- Lens subluxation, retinal detachment Skin-striae, hernias Other: Dural Ectasia, Spontaneous Pneumothorax

64. Contd.

65. Contd.

66. Contd.

67. Autosomal Dominant Affected individuals present in every generation Any child of an affected parent has a 50% of inheriting the condition Males and females are equally affected

68. Autosomal Recessive Both carriers are heterozygous The child of two heterozygous parents has a 25% chance of inheriting the gene Males and females are affected with equal frequency

69. Autosomal Dominant Disorders Achondroplasia Alexander disease Antithrombin deficiency Brugada syndrome Charcot-Marie-Tooth Syndrome Ehlers-Danlos Syndrome Familial hypercholesterolemia Fatal Familial Insomnia Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu Syndrome) Hereditary multiple exostoses Hereditary spherocytosis Huntington's Disease Hypertrophic cardiomyopathy Mandibulofacial dysostosis (Treacher Collins syndrome) Marfan Syndrome Mowat-Wilson Syndrome Multiple endocrine neoplasia Neurofibromatosis Osteogenesis Imperfecta Pfeiffer syndrome Polycystic Kidney Disease Tuberous Sclerosis Von Hippel-Lindau disease Familial adenomatous polyposis Noonan Syndrome Spinocerebellar Ataxia

70. X-Linked Recessive Disorders Red Green Color Blindness Hemophilia A, Hemophilia B Duchenne Muscular Dystrophy Alport Syndrome- Renal dz, hearing loss Charcot Marie Tooth-neuropathy causing muscles tissue and sensation loss Wiskott Aldrich Syndrome-eczema, thrombocytopenia, immune def., bloody diarrhea Fabry Disease- Lysosomal Storage Dz-burning extremity pain Hunter�s Syndrome-Lysosomal Storage Dz-hearling loss, thickend heart valves, OSA Lowe�s Syndrome-hydrophthalmia, cataracts, intellectual disabilities, aminoaciduria

71. What is this?

72. X- Linked Recessive Disorders Characteristics of X-linked recessive inheritance Males affected more commonly and severely than females Females are carriers but generally not affected. Affected males will only have affected daughters.

73. X-Linked Dominant Disorders Female carriers typically manifest abnormal findings An affected man will only have affected daughters and unaffected sons Some X-linked dominant disorders are lethal in males. Aicardi Syndrome- absent corpus callosum, the presence of retinal abnormalities, and seizures in the form of infantile spasms Incontentia Pigmenti- blistering, skin hyperpigmentation, and neurologic issues Rett Syndrome-developmental regression, writhing hand movements

74. Our last pedigree- What is this?

75. Mitochondrial Inheritance Diseases MELAS- Myopathy, Encephalopathy, Lactic Acidosis, and Stroke like episodes. MERRF- Myoclonic epilepsy associated with ragged red fibers. Kearns-Sayre Syndrome- ophthalmoplegia, pigmentary retinopathy, and cardiomyopathy.

76. Dysmorphology It is based on the fact that many structural defects represent errors in early embryonic or fetal development. Birth defects may be due to environmental exposures, genetic causes or a combination of external and genetic factors.

77. Fetal Alcohol Syndrome

78. Fetal Alcohol Syndrome Intrauterine and Postnatal Growth Retardation Height or weight < 10% FTT not caused by inadequate intake Disproportional low weight to height Deficient Brain Growth or Brain Malformation Structural brain abnormalities Head circumference < 10% Abnormal neuro examination Minor Facial Anomalies

79. Fetal Alcohol Syndrome

80. Sequences Pierre Robin Sequence: Secondary to hypoplasia of the mandibular area. Tongue becomes posteriorly located, preventing closure of the posterior palatal shelves. Can be a feature of other syndromes, such as Edwards and Stickler (autosomal dominant, early arthritis, ocular problems). Potter Sequence: Bilateral renal agenesis. Usually, history of oligohydramnios. Death not caused by renal failure but rather by pulmonary hypoplasia, as there is late development of alveolar specs. Potter facies consists of hypertelorism, epicanthal folds, low-set ears, micrognathia, a compressed, flat nose, and limb anomalies. Parents and siblings may have asymptomatic renal anomalies.

81. The End