Down syndrome and other chromosomal syndromes

This describes in detail Down syndrome and other syndromes due to chromosomal anomalies like Edward syndrome, patau syndrome and others. Mainly focusses on clinical features, epidemiology and treatment of these and also about genetics and genetic counselling

1. Down syndrome and other syndromes Dr.N.Rashmi Associate Professor, Pediatrics. JSSH

2. Down Syndrome Dr. John Langdon Down described the syndrome in 1866. Diagnosis was made clinically until 1959 The chromosome abnormality was discovered in 1959. Down syndrome is one of the first symptom complexes associated with mental retardation to be identified as a syndrome.

3. Down Syndrome Overview It is the most common pattern of human malformation with an incidence in the general population of 1 in 800-1000 live births. Over 350,000 people in the United States have Down syndrome. A high correlation exists between increasing maternal age and the presence of an extra chromosome in the offspring. Therefore, the expected rate of Down syndrome in a woman 20 years of age is 1 in 1,925 compared to an expected rate of Down syndrome in a woman 45 years of age of 1 in 20.

4. Genetics All persons with Down syndrome have duplicated chromosome 21 material The origin of the duplicated genetic material can vary Nondisjunction (about 96% of cases) The extra chromosome may arise by abnormal sorting to produce an extra, free-standing chromosome ( trisomy 21) Translocation (3 % of cases) a joining of chromosomes to produce extra chromosome 21 material that is attached to another chromosome Mosaicism (1-2%) Patients with mixtures of normal and trisomic cells (mosaic Down syndrome) often have milder phenotypes. Percentages of normal cells within the blood sample used for chromosome studies may differ from the percentages of normal cells in other tissues like brain or heart.

5. Trisomy 21 Karyotype

6. Extensive mapping of genes on this "critical region" of chromosome 21 is under way as part of the human genome initiative. The mechanisms by which increased dosage of these genes leads to the Down syndrome phenotype are as yet unknown.

7. Clinical Features Head and neck Brachycephaly Up-slanting palpebral fissures Epicanthal folds Brushfield spots Flat nasal bridge Folded or dysplastic ears Open mouth Protruding tongue Short neck Excessive skin at the nape of neck Extremities Short broad hands Short fifth finger Incurved fifth finger Transverse palmer crease Space between first and second toe Hyper flexibility of joints

8. Clinical Features Extra and loose neck skin Single creases on the palms Clinodactyly (curved fifth finger) Broad space between the first and second toes A deep plantar crease The tongue often protrudes, more because of low muscle tone than true enlargement.

9. Clinical Features Central hair whorl (cowlick) Flat occiput (back of the head) Upslanting eyes Epicanthal folds (folds around the corner of the eye) White spots in the iris of the eye (Brushfield spots) Upturned nose

10. Clinical Features As with all syndromes, the pattern of minor and major defects in Down syndrome varies from individual to individual. None of the anomalies taken alone are specific or diagnostic for Down syndrome. When Down syndrome is suspected, a chromosome study (karyotype) will confirm or exclude the diagnosis.

11. Neonatal features Flat facial profile Poor Moro reflex Excessive skin at the nape of neck Slanted palpebral fissures Hypotonia Hyper flexibility of joints Dysplasia of pelvis Anomalous ears Dysplasia of midphalanx of fifth finger Transverse palmer crease

12. Related Conditions Congenital Heart Disease Seizures Eye Anomalies Hearing Loss Genito-Urinary Tract Anomalies Respiratory Disease Obesity Sleep Apnea Developmental Delays Blood Disease Endocrine Disease Blood Disorders Alzheimer’s Disease

13. Heart Defects 40% of individuals with Down syndrome have some form of congenital heart defect AV ( atrioventricular ) Septal defect Ventricular Septal Defect (VSD) Patent Ductus Arteriosus (PDA) Atrial Septal Defect (ASD) Tetralogy of Fallot Aberrant Subclavian Artery Pulmonary Hypertension Adolescents and young adults can develop heart valve dysfunction even when they have had no history of congenital heart problems. SBE prophylaxis may be necessary.

14. Ophthalmologic Features Brushfield spots (speckling of the iris) Fine Lens Opacities Nystagmus Strabismus Keratoconus Ptosis Cataracts Astigmatism Hyperopia (far sightedness) Myopia (near sightedness) Blepharitis Tear Duct Obstruction

15. Ophthalmologic Features Brushfield Spots Keratoconus

16. Hearing Loss Can be conductive, sensorineural or both Can be unilateral or bilateral Often undiagnosed Change in learning or behavior-consider hearing screen Etiology can be multifactorial Narrow posterior throat structures Subtle immune deficiency resulting in recurrent ear infections

17. Gastrointestinal Disease Pyloric stenosis Tracheo-esophageal fistula Esophageal atresia (obstruction of the esophagus) Duodenal atresia (obstruction of the duodenum). Gastroesophageal Reflux (GERD) Constipation Hirschprung’s disease Celiac disease Imperforate Anus Neonatal Liver Disease (rare)

18. Respiratory Disorders Otitis media Sinusitis Pneumonia Sleep apnea Dysphagia/oromotor dysfunction Aspiration Pulmonary Hypertension

19. Dental Diseases Microdontias Missing Teeth/Fused Teeth Delayed tooth eruption (1-2 years later than average) Malocclusions Periodontal disease Gingivitis leading to loss of Alveolar bone Dental Caries occur with lower prevalence than in the general population

20. Genitourinary Tract Anomalies Micropenis Cryptoorchidism Infertility Cystitis/Urinary Tract Infections Renal Anomalies Wilm’s Tumor

21. Endocrine Disorders Congenital hypothyroidism Thyroid Disease Diabetes Failure to Thrive- in infancy and early childhood Obesity Short Stature Lipid abnormalities

22. Blood Disorders Immune Dysfunction Myeloid Proliferation Leukemia 1 in 150 in children with Down syndrome compared with 1 in 2800 in children at large Platelet Disorders White blood cell impairment Erythrocytosis (secondary to chronic hypoxia)

23. Skin Conditions Most related to Immune dysfunction/Inflammatory response Atopic Dermatitis (eczema) Seborrheic Dermatitis Vitiligo Chelitis Ichthyosis Xerosis Alopecia Areata Syringomas Onychomycosis

24. Growth BW, length and HC are less in DS Reduced growth rate Prevalence of obesity is greater in DS Weight is less than expected for length in infants with DS, and then increases disproportion ally so that they are obese by age 3-4 yrs

25. Reproduction Women with DS are fertile and may become pregnant. Nearly all males with DS are infertile. The mechanism is impairment of spermatogenesis

26. The Neurology of Down Syndrome The nervous system is always affected in Down syndrome.  Developmental Delays Hypotonia Atlantoaxial instability Symptomatic -vs- Asymptomatic Seizures Mental Health Disorders Alzheimer’s Disease

27. Brain pathology Slightly smaller brain size for age. Shorter diameter for the anterior-posterior brain measurement. An unusually steep slope to the posterior portions of the brain. Insufficiently developed superior temporal gyrus . It is not known in what way these features contribute to the developmental disabilities of Down syndrome.

28. Neurodevelopmental and behavior Impairments Aggressive Behavior (7%) ADHD (6%) Conduct/Oppositional Disorder (5%) Anxiety Disorders (5%) Self Injurious Behavior ( 1%) Autism (1%)

29. Seizures Seizures occur in 6% of individuals with Down syndrome Most common seizure type is generalized tonic clonic Age of onset typically bimodal distribution Onset before age 3 Onset after age 13

30. Neurologic Language Delays Receptive language tends to be better than expressive Central Hypotonia Gross motor Delays Oral motor dysfunction Poor oral motor coordination Decreased sensory awareness

31. Most people with Down syndrome have some level of intellectual disability. The level usually falls into the mild to moderate range. Not indicative of the many strengths and talents that each individual possesses. Children with Down syndrome learn to sit, walk, talk, play, toilet train and do most other activities only somewhat later than their peers without down syndrome.

32. Diagnosis Prenatal screening If no screening – It is recognized from the characteristic phenotypic features. Confirmed by Karyotype.

33. Management 1. Growth – Measurements should be plotted on the appropriate growth chart for children with DS. This will help in prevention of obesity and early diagnosis of celiac disease and hypothyroidism. 2. Cardiac disease – All newborns should be evaluated by cardiac ECHO for CHD in consultation with pediatric cardiologist. 3. Hearing – Screening to be done in the newborn period, every 6 months until 3 yrs of age and then annually.

34. Management (cont.) 4. Eye disorders - An eye exam should be performed in the newborn period or at least before 6 months of age to detect strabismus, nystagmus , and cataracts. 5. Thyroid Function – Should be done in newborn period and should be repeated at six and 12 months , and then annually. 6. Celiac Disease – Screening should begin at 2 yrs. Repeat screening if signs/ Sx develop.

35. Management ( cont) Hematology – CBC with differential at birth to evaluate for polycythemia as well as WBC. Atlanto -axial instability – X ray for evidence of AAI or sub- luxation at 3 to 5 years of age. Alzheimer’s disease – Adult with a Down Syndrome has earlier onset of symptoms. When diagnosis is considered, thyroid disease and possible depression should be excluded.

36. Early intervention services, which begin shortly after birth, help children with Down syndrome develop to their full potential. Quality educational programs, along with a stimulating home environment and good medical care enable people with Down syndrome to become contributing members of their families and communities.

37. Early Intervention Works! Just a decade ago, the prognosis for these children was not as bright as it is today. Early Intervention programs from birth to age 3 have shown impressive results. Families receive training in how to help their children learn to maximize the development that occurs in the early years. In addition, many children receive: PT OT Speech Therapy Aqua therapy Hippotherapy Music therapy Infant education individually and in groups

38. Mortality Median age of death has increased from 25 yrs in 1983 to 49 yrs in 1997, an average of 1.7 yrs increase per year. Most likely cause of death is CHD, Dementia, Hypothyroidism and Leukemia. Improved survival is because of increased placements of infants in homes and changes in treatment for common causes of death. Survival is better for males and blacks.

39. Counselling May begin when a prenatal diagnosis is made. Discuss the wide range of variability in manifestation and prognosis. Medical and educational treatments and interventions should be discussed. Initial referrals for early intervention, informative publications, parent groups, and advocacy groups.

40. Trisomy 18 or Edward's Syndrome

41. How does the disorder occur? Trisomy 18, or Edward's syndrome, is the second most common trisomy after Down's syndrome. Edward's syndrome occurs when three sets ( trisomy ) of chromosome 18 occur. Trisomy 18 is therefore caused by a genetic abnormality occurring before conception, when egg and sperm cells are made. A healthy egg or sperm cell contains 23 individual chromosomes - one to contribute to each of the 23 pairs of chromosomes needed to form a healthy, 46 chromosome cell. However, sometimes egg and sperm cells are left with 24 (or more) chromosomes. It is the joining of these egg or sperm cells that eventually cause a trisomy fetus to be formed.

42. A Brief History of the Disorder Trisomy 18 was discovered by John Hilton Edwards, a British geneticist, in 1960. His discovery of it led to the association of his name with the syndrome. Edwards (b 1928) served as professor of human genetics at Birmingham University from 1969 to 1979 and at Oxford University from 1979 to 1995. He was the author of Human Genetics (1978) as well as numerous papers on a variety of topics in the field.

43. CanTrisomy 18 Be Passed to Future Generations? Because Trisomy 18 is caused by non-disjunction, it cannot be passed on to future generations. In addition, babies diagnosed with Edwards syndrome rarely live past 5-6 days; fetuses identified with Trisomy 18 are often miscarried or aborted.

44. Type of Mutation: Trisomy 18 is a gene mutation which is caused by an extra 18th chromosome Where does it occur in a karyotype/chromosome/gene? It occurs in the 18th chromosomal pair

45. What Are the Phenotypic Effects to the Human Body? Most children born with Edwards' syndrome appear weak and fragile, and they are often underweight. The head is unusually small and the back of the head is prominent. The ears are malformed and low-set, and the mouth and jaw are small (also known as micrognathia ). The baby may also have a cleft lip. Often, the hands malformed, clenched into fists with the index finger overlapping the other fingers. The child may have club feet, and toes may be webbed or fused. A number of problems involving the internal organs may be present. Abnormalities often occur in the lungs and diaphragm, and blood vessel malformations are common. Various types of congenital heart disease may be present. The child may have an a hernia, malformed kidneys, and abnormalities of the urogenital system, such as undescended testicles in a male child ( cryptochordism ).

46. How Is it Diagnosed? Edwards' syndrome at birth may be diagnosed by the physical abnormalities characteristic to the syndrome. In addition, physical examination of the infant may show arched type fingerprint patterns and xrays may reveal a short breast bone. Definitive diagnosis is achieved through karyotyping , which involves drawing the baby's blood for a microscopic examination of the chromosomes. Using special stains and microscopy, individual chromosomes are identified, and the presence of an extra chromosome 18 is revealed. Edwards' syndrome can be detected before birth. If a pregnant woman is older than 35, has a family history of genetic abnormalities, has previously conceived a child with a genetic abnormality, or has suffered earlier miscarriages, she may undergo tests to determine whether her child carries genetic abnormalities. Potential tests include maternal serum alpha-fetal protein analysis or screening, ultrasonography , amniocentesis, and chorionic villus sampliing . In addition, a pregnant woman carrying a child with Edwards' syndrome may have an unusually large uterus during pregnancy, due to the presence of extra amniotic fluid. An unusually small placenta may be noted during the birth of the child .

47. How Is it Treated? There is no cure for Edwards syndrome. Ninety to 95 % of all babies born with it die within a year of birth. The few infants that do survive need special treatment--ranging from muscular therapy to nervous system and skeletal corrections--for their various handicaps.

48. Effects Edwards Syndrome is a  rare genetic disorder caused by an extra copy of chromosome18. Infants born with this syndrome have;  growth deficiency, low birth weight, an odd shaped head, a small mouth and jaw, webbed fingers, mental retardation, organ abnormalities, and heart defects.

49. Pictures.

50. The Chromosome that is effected.

51. Pedigree

52. Symptoms Clenched hands Crossed legs (preferred position) Feet with a rounded bottom (rocker-bottom feet) Low birth weight Low-set ears Mental deficiency Small head Small jaw Underdeveloped fingernails Unusual shaped chest

53. Treatment Depending on the individuals condition, is how the doctors proceed with treatment.

54. Facts It occurs in about 1 out of every 3000 live births.  Less than 10 percent live past their first birthdays. Mainly seen in girls.

55. Patau Syndrome A picture demonstrating polydactyly, or extra fingers, a common abnormality in Patau syndrome.

56. Description Patau syndrome - also known as trisomy 13 and trisomy D. Affects about 1 in 12,000 live births. More than 80% of infants with Patau syndrome die within their first year of life. Cayden Phipps: 3A - Abrams 66 The Simian line , or an abnormal palm pattern that is usually a symptom of Patau syndrome.

57. History Patau syndrome, or “ Trisomy 13 ”, as it was first called, was first observed by Thomas Bartholin in 1657. However, the actual genetic and chromosomal-related parts of it were discovered by Dr. Klaus Patau in 1960, hence the name “ Patau syndrome ”. Cayden Phipps: 3A - Abrams 67

58. Cause Each cell in the body has two copies of chromosome 13, one from each parent. However, with Patau syndrome, the cells have three copies of chromosome 13 instead of the normal two, as well as extra material from the extra chromosome attached to another chromosome, resulting in changes. Most cases are not inherited, but occur as random events during the formation of gametes. An error in meiosis may result in gametes with an abnormal number of chromosomes. One way this will occur is with the gamete having an extra chromosome 13. Cayden Phipps: 3A - Abrams 68 As you can see here, there are three chromosome 13’s. Normally, there would be two, one from each parent’s gamete, but a mutation/error in cell division gives the gamete an abnormal number of chromosomes.

59. Mosaic Patau A small percentage of cases occur when only some of the body’s cells have an extra copy of chromosome 13, resulting in a mixed population of cells with differing numbers of chromosomes. This is called Mosaic Patau. Cayden Phipps: 3A - Abrams 69 A baby with a cleft palate, a common abnormality of Patau syndrome.

60. Common Problems Nervous system problems: Mental and motor disabilities similar to that of autism Microcephaly, or a less rounded brain resulting in more of an egg-shaped skull Eye structure defects: Microphthalmia, or crossed eyes (may involve one eye or both) Cataracts Sensory Nystagmus, or involuntart “twitching” of the eye Optic nerve hypoplasia, or the underdevelopment of the optic nerve Cayden Phipps: 3A - Abrams 70 Sensory nystagmus

61. Common Problems cont. Muscular and skin problems: Polydactyly, or extra fingers/toes Low-down ears Prominent heels and deformed feet, called ‘rocker-bottom’ feet Strange palm patterns, commonly called the Simian line Overlapping of the fingers over thumb Cleft palate Cayden Phipps: 3A - Abrams 71 Polydactyly The Simian line ‘Rocker-bottom’ feet

62. Common Problems, cont. Vascular Problems: Kidney problems Heart defects such as ventricular septal defect Cayden Phipps: 3A - Abrams 72 Kidney Problem The disease shown right is called Polycystic kidney disease (PKD). This is a disorder in which clumps of cysts develop within your kidneys. Cysts are small round sacs containing water-like fluid.

63. Treatment There is no treatment to address the condition. However, there are procedures to sustain life for a bit. Most times, surgery is required to fix defects to allow the child to survive for as long as possible. Since most infants with Patau syndrome die within the first year of life, special management/procedures are necessary; this is very complex and carefully laid out. Many children have trouble surviving the first few days or weeks of life due to severe neurologic and vascular problems. Cayden Phipps: 3A - Abrams 73

64. CRI DU CHAT Syndrome

65. What is CRI Du Chat syndrome? Cri du chat syndrome is a group of symptoms that result from missing a piece of chromosome number 5. Cri Du Chat is based on the infant’s cry, which is high pitched sound like a cat.

66. On Which chromosomes does the mutation occur? Cri du chat syndrome is rare. It happens when genetic information on chromosome 5 is missing . One missing piece, called TERT (telomerase reverse transcriptase)

67. Cri-du-chat is caused by a deletion (the length of which may vary ) on the short arm of chromosome 5. short arm of chromosome 5. Cri du chat syndrome occurs every 1 per 200000-500000 newborns. How does it occur and How often does it occur?

68. How many people die from Cri Du Chat each year? Although there is no cure for Cri Du Chat disease but the disease is not fatal. The majority of cases have good survival expectations (in an Italian study, the oldest patient was aged 61 years)4 although about 10% of cases die in the first year of life.

69. Cry that is high-pitched and sounds like a cat Downward slant to the eyes Low birth weight and slow growth Low-set or abnormally shaped ears Mental retardation Partial webbing or fusing of fingers or toes Single line in the palm of the hand (simian crease) Skin tags just in front of the ear Slow or incomplete development of motor skills Small head (microcephaly) Small jaw (micrognathia) Wide-set eyes . Symptoms

70. What is the probability of it being passed from one generation to the next? Most cases of cri-du-chat syndrome are not inherited. The deletion occurs most often as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. About 10 percent of people with cri-du-chat syndrome inherit the chromosome abnormality from an unaffected parent. Here is a regular parent and here is a victim, child of Cri Du Chat.

71. Is there a treatment for Cri Du Chat? No specific treatment is available for this syndrome. The mental retardation must be addressed, and counseling is recommended Parents of a child with this syndrome should have genetic counseling and a karyotype test to determine if one parent has a rearrangement of chromosome 5.

72. What is the prevention for Cri Du Chat? There is no known prevention. Couples with a family history of this syndrome who wish to become pregnant may consider genetic counseling .

73. Cri-du-Chat was discovered by Jerome Lejeune in 1963. Jerome Lejeune, a French geneticist who discovered the chromosome abnormality in humans that causes Down syndrome, a common form of mental retardation . Who discovered the Cri Du Chat Syndrome?

74. What are some other names for Cri Du Chat Syndrome? •Cat cry syndrome •Chromosome 5p- Syndrome •5p deletion syndrome •monosomy 5p •5p- syndrome Cry of the cat

75. If a child has this unusual cry or other features seen in cri du chat syndrome, chromosome testing should be performed. Chromosome analysis provides the definitive diagnosis of cri du chat syndrome and can be performed from a blood test . Chromosome analysis, also called karyotyping, involves staining the chromosomes and examining them under a microscope. In some cases the deletion of material from chromosome 5 can be easily seen . How do you Strongly Diagnosis Cri Du Chat?

76. Is Cri Du Chat result of Mutation? Cri du Chat is a genetic mutation caused by the spontaneous deletion of material on one of the arms of the 5th chromosome. There are several variants of the disorder that results, and although it is genetic in cause it does not appear to be an inherited disorder but a spontaneous mutation which happens during early embryonic development.

77. Turner’s Syndrome

78. What is Turner’s Syndrome? Also referred to as Monosomy X An abnormal genetic condition resulting from a defect on or absence of the second sex chromosome

79. Common Names monosomy X Ullrich-Turner syndrome 45 X Mosaic Turner syndrome Gonadal dysgenesis

80. What’s the defect? Female is missing an X-chromosome

81. Cause The female is born without the second X chromosome "45X” meaning that an individual has 44 autosomes and a single X chromosome Multiple blood cells are required to be tested because some cells may carry an X monosomy while others may not

82. Type of Disorder Chromosomal condition Turner’s syndrome is neither recessive or dominant, it’s a condition that causes infertility and immature sexual development in women, it is due to the possession of only one X chromosome, instead of the two always present in normal women.

83. KARYOTYPE

84. How does it happen? Usually caused by non-disjunction Pair of sex chromosomes does not separate during formation of either egg or sperm When abnormal egg unites with normal sperm to form embryo… May end up missing that sex chromosome Be X instead of XX

85. How common is Turner’s syndrome Turner’s syndrome occurs in about 1 in 2,500 live births 10% of spontaneously aborted fetuses have this disorder

86. Turner’s syndrome baby

87. Symptoms Shorter than average/slow growth rate No growth spurts during puberty Non-functioning ovaries No production of estrogen or progesterone Infertility Middle Ear infections leading to eventual loss of hearing Problems with math, memory skills, and fine-finger movements Discolored spots on skin

88. Symptoms Cont. Wide/webbed neck Low hairline Broad chest/widely spaced nipples Arms turned out at elbows Heart murmur due to narrowing of aorta High blood pressure Minor vision issues Scoliosis Osteoporosis (thinning of bones) due to lack of estrogen

89. Symptoms Visual

90. Physical Symptoms Short stature (Usually no taller than 4’8”) Obese weight (due to an underactive thyroid) Drooping eyelids Problems with breast development Short fingers and toes Extra skin on the neck (webbed neck ) Swelling of the hands and feet Low set ears Soft nails that turn upward at the ends Irregular rotation of wrist and elbow joints

91. Internal Symptoms Loss of ovarian functions (infertility) Heart defects Kidney problems Visual impairments Ear infections and hearing loss High blood pressure Weak bones

92. Mental Symptoms Range of intellectual development usually normal However, they seem to have difficulty with specific skills Learning disabilities Especially in math Behavioral problems Problems with concentrating and remembering

93. When and how to test for it Turner syndrome can be diagnosed at any stage of life. It may be diagnosed before birth if chromosome analysis is done during prenatal testing. The doctor will perform a physical exam and look for signs of underdevelopment. The following tests may also be performed: Blood hormone levels Echocardiogram Karyotyping MRI of the chest Ultrasound of reproductive organs and kidneys Pelvic exam Turner syndrome may also alter various estrogen levels in the blood and urine.

94. Diagnosis Women can be amniotic fluid tested while pregnant If the test returns back to be positive, genetic counseling is recommended A simple blood test karyotype can determine the diagnosis Usually diagnosed during infancy but can be diagnosed later in life

95. Statistics It currently affects 60,000 women in the United States For unknown reasons 98% of Turner Syndrome-afflicted fetuses spontaneously abort, thus making up 10% of all miscarriages Occurs in about 1/2,000 live female births

96. Effect on Life Women with Turner’s Syndrome lead typical lives Have normal family relations Often bullied when young due to appearance Turner’s Syndrome Support Groups

97. Treatment/Cure No cure for Turner’s Syndrome Are certain treatments to help with the symptoms Growth hormone therapy Estrogen/progesterone replacement Close heart monitoring for heart problems

98. Remember… We are all people and we are all different in our own ways. Just because some of us may look or act different in your eyes does not give you the excuse to make fun of them. RESPECT EVERYONE FOR THEIR DIFFERENCES

99. Support Groups There is a support group called “Short Happens!” There are also many support groups online for younger girls to talk about living with Turner’s Syndrome.

100. Interesting Facts Most girls that go untreated only grow to 4 feet 8 inches Discovered in 1938 by Dr. Henry Turner 800 new cases of Turner's syndrome are reported yearly in the United States

101. Noonan’s Syndrome

102. What is Noonan’s Syndrome? Noonan’s Syndrome (NS) is a relatively Common congenital genetic condition which affects both males and females. It prevents normal development in various parts of the body.

103. Noonan’s Syndrome (con’d) The history of NS begins with a woman named Dr. Jacqueline Noonan. In 1962, Noonan presented at Midwest Society for Pediatric research a clinical study of associated non cardiac malformations in children with congenital heart disease and describes nine patients who shared similar physical disorders.

104. What is Noonan’s Syndrome (con’d) Dr. John Opitz proposed that Noonan’s Syndrome be given the name because Dr. Jackie Noonan was the first to recognize and describe the condition that occurred in both sexes.

105. What causes Noonan’s Syndrome? NS is caused by a genetic mutation and is acquired when a child inherits a copy of an affected gene from a parent. There is 1 case per 1000 to 1 case per 2500 live births. The disorder is present from birth, but age impacts the facial phenotype. Infants with Noonan syndrome can be difficult to recognize by facial appearance alone. The phenotype becomes more striking in early childhood, but with advancing age, it may again become quite subtle. Careful examination of an affected child's parents may in fact reveal that they are mildly affected.

106. Physical Features Children Could Have There is a whole list of Noonan’s Syndrome: Heart abnormalities Joints and Muscles Feeding Bruising and Growth Bleeding Hearing Puberty Lymphatic System

107. Development, Behavior, and Intelligence The age at which developmental milestones are achieved may be delayed. For example, the approximate age of sitting alone is 10 months and walking unaided 21 months. Around 10% of children with Noonan Syndrome require significant special education. It should be noted that Noonan Syndrome is not usually associated with severe learning difficulties. No specific behavioral pattern has been identified, however individuals have been reported to show signs of clumsiness, stubbornness, and irritability.

108. Noonan’s Angels

109. Webbed Neck

110. Klinefelter syndrome

111. Overview Klinefelter syndrome is the presence of an extra X chromosome in a male.

112. What is Klinefelter’s Syndrome? Klinefelter's syndrome is a genetic disorder that only affects males. It occurs when a boy is born with one or more extra X chromosomes, which causes a boy to produce less testosterone than a normal boy. . Due to having an extra X chromosome, the male may possibly have some physical traits unusual for males.

113. What is Klinefelter’s Syndrome? Instead of an XY sex chromosome pattern that most males have, these males have an XXY pattern. Some people with Kleinfelter’s consider themselves to be transgender, intersexed, or transsexual, due to having a more feminine appearance and/or feminine emotions.

114. Other Names for Klinefelter’s: 47, XXY XXY Syndrome XXY Trisomy Or 3+X Chromosomes with Y Frequency of Klinefelter’s: Approximately 1 in 500 to 1,000.

115. How do you get Klinefelter’s Syndrome? An extra X chromosome most often occurs when the genetic material in the eggs or the sperm splits unevenly. It’s a random event during the formation of reproductive cells An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. It’s diagnosed in adulthood by using a karyotype.

116. Symptoms of Klinefelter’s Syndrome Physical Symptoms: Long legs Wide hips Enlarged breasts Sparse body hair Small testicles Less muscular Weaker bones

117. Symptoms of Klinefelter’s Syndrome Language Symptoms: Learn to talk late Trouble expressing thoughts and needs Problems reading Trouble processing what they hear Other Symptoms: Normal sex lives, but cannot father children Produce much less testosterone

118. Treatment of Klinefelter’s Syndrome Males with Klinefelter’s Syndrome can be given testosterone therapy. If given around the age of puberty, it can help a boy have normal body development. A infertility specialist may be able to help a male with Klinefelter’s syndrome to get a woman pregnant.

119. History of Klinefelter’s Syndrome In 1942, Klinefelter’s was discovered by Dr. Harry Klinefelter, along with other doctors at General Hospital in Boston. Doctors reported a group of males with “enlarged breasts, sparse facial and body hair, small testes, and inability to produce sperm.” By the late 1950’s, researches discovered that these men had an extra sex chromosome thus having the pattern XXY.

120. Lifestyle with Klinefelter’s Syndrome As a Baby, Child, and Teen: May sit up, crawl, and walk later than other infants. Tend to be taller and have less muscle control than other boys. May have language problems Tend to be quiet and undemanding. Entering puberty, these males don’t make as much testosterone.

121. Lifestyle with Klinefelter’s Syndrome As an Adult: Look similar to normal males, but are often taller. Likely to have health problems such as breast cancer, vein diseases, tooth decay, and autoimmune disorders. Cannot father children due to infertility. May have a harder time doing work that involves reading and writing. Normal social life with friends and family.

122. Complications *Attention deficient hyperactivity disorder *Autoimmune disorders such as lupus, rheumatoid arthritis, and Sjogren syndrome *Breast cancer & Depression *Dyslexia Varicose veins * Extragonadal germ cell tumor (a rare tumor) *Learning disabilities, despite normal or high IQ *Lung disease & Osteoporosis

123. Tests & diagnosis * Karyotyping *Semen count *Serum estradiol levels (a type of estrogen) *Serum follicle stimulating hormone *Serum luteinizing hormone*Serum testosterone Adults may come to the doctor because of infertility. School-age children may be brought in to because of learning problems. The following tests may be performed:

124. Prognosis Most patients have a normal, productive life.

125. Marfan’s Syndrome

126. What is Marfan’s Syndrome? Marfan’s Syndrome is a genetic disorder that afftects 1 in 10,000 individuals. This disorder affects the body’s connective tissue. It is a malformation of Chromosome 15, the part that is used to produce this tissue.

127. What is Marfan’s Syndrome? It usually occurs equally in males and in females. It is life threatening.

128. Symptoms One of the symptoms of this syndrome is that people with it usually tend to develop an enlargement of the aorta, the main blood vessel that takes blood from the heart to the rest of the body. Another symptom is that many people are very tall and thin.

129. Symptoms Also many individuals develop abnormal growth of their chest. One other symptom is that individuals with this syndrome experience trouble with there sight, due to retinal detachment. Many people with this syndrome grow up to 7’ or taller.

130. Who is affected by Marfan’s? Many people are affected by this syndrome and many of those affected by this kind of syndrome are athletes. Some of them use this syndrome to their advantage, especially basketball and volleyball players.

131. Due to Marfan’s Syndrome many athletes sometimes die without warning. The average age of death for people with Marfan’s Syndrome is 32.

132. What Is The Cause of Death? The cause of death in people with Marfan’s Syndrome are complications with the heart. Since the aorta is enlarging and thinning, the aorta might tear and the aortic valve might also start a leak, thus leading to heart failure.

133. Cures?? Doctors suggest using beta blockers to cure or try to treat this syndrome. Doctors also suggest for you to do an aortic valve replacement.

134. D escription Heritable disorder of the connective tissue . Not tied to any particular sex, race, or ethnic group 1 in 10000 incidence Caused by a mutation in the FBN1 gene that determines the structure of fibrillin Fibrillin1 is an extracellular matrix glycoprotein that polymerizes to form microfibrils in connective tissue and elastic fibers in multiple parts of the body such as bones , joints , eyes , blood vessels , and heart .

135. FBN-1 Gene Located on chromosome 15 . Marfan syndrome is caused by over 100 different mutations on FBN1 Mutations scattered across the gene and each family has it’s unique mutation .

136. Defective Fibrillin 1 Protein Amount of fibrillin 1 protein produced by cells is reduced . Structure and stability of protein is affected . Transport of fibrillin 1 protein out of the cell is impaired . Amount of fibrillin 1 reduced means decreased microfibril production . Less microfibril leads to more active TGF-beta , which leads to Marfan’s symptoms .

137. Basic Genetic Information 25-35 % de novo mutations . Autosomal Dominant . Dominant negative Mutation – the altered gene product antagonizes the product of the normal gene (mutant fibrilin1 inhibits formation of normal microfibrils by normal one or stimulates proteolysis of EC microfibrils )

138. The phenotype is consistent within a family although the severity of phenotype may vary considerably . So , intrafamiliar and interfamiliar variability suggest that environmental and epigenetic factors play a significant role in determining the phenotype . The disease show age dependent development of the manifestations .

139. Fibrillin-1 mutation causes several Marfanlike disorders such as : the mitral valve prolapse . aortic dilation . (MASS) phenotype ( myopia,mitral valve prolapse skin, and skeletal features ) . or isolated ectopia lentis .

140. Clinical picture Skeleton A tall, slender body build. Long arms, legs, fingers, and toes ( arachnodactylyl ). A person’s arm span (the distance from the fingertips of one hand to the fingertips of the other with the arms stretched out from the sides) may be greater than his or her height. A receding lower jaw, causing an overbite. A protruding or sunken chest. A curved spine. Flat feet that are rotated inward

141. Eyes Off-center or dislocated lenses . Retinal detachment . Skin Stretch marks with increased risk for abdominal hernias .

142. Heart and Blood vessels The major cause of death from this disease . Abnormally large mitral valve leaflets Mitral regurgitation Weakened middle layer of aortic wall so , aneurysm may form Tears in inner and middle aortic layers .

143. Dural ectasia a hallmark of Marfan syndrome that is very rare in the general population. ( 65-92% )

144. Pulmonary findings Spontaneous pneumothorax (about 5% of patients) Apical blebs on chest radiography Sleep apnea . This may be due to looseness of the connective tissue in the airways.

145. D iagnosis The diagnosis cannot be based on molecular analysis alone because molecular diagnosis is not practically availiable as allelic heterogeneity makes identification of the causative mutation in each family prohibitively labor-intensive and because of the lack of reliable genotype-phenotype correlation. Marfan syndrome is currently diagnosed using criteria based on an evaluation of the family history , molecular data , and 6 organ systems .

146. Berlin criteria Marfan syndrome was diagnosed on the basis of involvement of : the skeletal system 2 other systems at least   one major manifestation (ectopia lentis, aortic dilatation or dissection, or dural ectasia )

147. Ghent criteria Revised in 1995 based on clinical observation of various organ systems and on the family history.

148. Testing and Diagnosis Genetic diagnosis For at risk individuals , in families segregating the disease by detecting the mutations when it happens to be known . Prenatal diagnosis available only in families in which the mutation is known .

149. Testing and Diagnosis Imaging tests Chest x-ray MRI

150. Life Expectancy For woman, life expectancy has risen from 49 to 74 years . For men, life expectancy has risen from 41 to 70 years in the last 32 years . This life expectancy of Marfan patients is now about that of and average person, this has grown because there is currently better treatment for Marfan Syndrome .

151. Any questions???