Common Genetic Syndromes and their Medical Consequences

1. Common Genetic Syndromes and their Medical Consequences Nicole P. Safina MD, FAAP, FACMG Assistant Professor of Pediatrics and Genetics

2. Common Genetic Syndromes • Review • Diagnosis • Prognosis • Genetics of Syndrome • Medical Complications • Impact on patient/family

3. Incidence of Common Syndromes • Down Syndrome 1/700 • Noonan Syndrome 1/1000-3000 • Turner Syndrome 1/5000 • Neurofibromatosis I 1/3000 • 22q11 Deletion 1/4000 • Achondroplasia 1/ 15,000-40,000 • Fragile X 1/3600 males, 1/6000 females

4. Down Syndrome • 1/650-700 births most common aneuploidy; most common cause of genetic MR • Langdon Down in 1866; 1959 the chromosome cause became clear • Etiology: maternal nondisjunction (90%) rarely paternal nondisjunction; chromosome translocation (5%), mosaic (<5%) • Increase risk with increase maternal age or parent is a translocation carrier • Risk of reoccurrence typically depends on mother’s age for full trisomy

5. Trisomy 21 Robertsonian translocation 47, XX,+21 46, XY, rob (14;21), +21

6. Down Syndrome phenotype

7. Down Syndrome

8. Down Syndrome infant-child • 85% survive to 1 year and 50% live >age 50 • 30-50% CHD with endocardial cushion defects most common (Atrioventicular canal) • Gastroesopageal reflux, otitis media, mixed hearing loss • Ophthalmologic abnormalities: strabismus, cataracts glaucoma • Increased risk of leukemia (10-50 times) • Hypothyroidism (30%) • Hirschsprung disease • Increased risk for epilepsy

9. Down syndrome Intestinal Atresias • Duodenal atresia, esophageal atresia • Usually present with bilious vomiting in the newborn period, double bubble sign

10. C1-C2 instability/dislocation C1 laxity of the transverse ligament (13-14% instability)

11. Development • Developmental delay obvious after first year • IQ 20-85; Significant variability among children • Early infant toddler connection • Most children require special education, some can be mainstreamed

12. Down Syndrome (older childhood-teenager ) • Increased risk of sleep apnea (mid face hypoplasia, adenoid hypertrophy) • Celiac disease • Large adenoids sleep apnea, airway obstruction • Hypothyroidism • Early adulthood: obesity, insulin resistance, premature cardiovascular disease

13. Aging and Down Syndrome • Premature senility associated with characteristics of Alzheimer disease (AD) • Up to 10-25% show signs of AD before age 50 and up to 50% before the 6th decade • Cortical atrophy, ventricular dilation, neurofibrillar tangles • AD affects Down Syndrome patients at an earlier age than general population • Increased risk of testicular cancer

14. Society and Culture • Acceptance in family dynamic and society can impact overall development (parenting , support groups) • Starts in prenatal setting • Education, housing and work environments • Medical professionals play a major role to help shaping public attitudes • National Association of Down Syndrome[1960]

15. Noonan syndrome • One of the most common genetic disorders with congenital heart defect (1/3000) • Wide range of clinical variability and phenotype expression • Autosomal dominant with normal chromosomes • NOT the ‘male Turners syndrome’ • Affect male and females equally

16. Noonan syndrome: features • Broad, short or webbed neck • Unusual chest shape with superior pectus carinatum, inferior pectus excavatum • Apparently wide low-set nipples • Cryptorchidism in males • Down slanting palpebral fissures, ptosis, low set ears • Congenital heart defect , hypertrophic cardiomyopathy • Developmental delay of variable degree, hypotonia • Increased incidence of malignancy

17. Noonan syndrome

18. Noonan Syndrome • Pulmonic stenosis often diagnosed in infancy (20-50%) • Cardiomyopathy (20-30%) may present at birth or develop in childhood • Lymphatic dysplasia and cystic hygroma can be present • Coagulation abnormalities

19. Noonan syndrome • Diagnosis can be missed if features are subtle • Failure to thrive with GE reflux present in infancy; FTT self limited • Short stature late childhood adolescence sometimes with growth hormone deficiency; mean female ht 150 females, 160 males

20. Noonan: Inheritance • Autosomal dominant 30-75% will have an affected parent • PTPN11 (50%) • SOS1 (16-20%), RAF1 (3-17%) • KRAS <5% • SHOC2, NRAS <5% • Clinical diagnosis

21. Autosomal Dominant Inheritance • Affects males and females equally • “Vertical” transmission (one generation to the next) • High spontaneous mutation rate • 50% reoccurrence risk for affected child when parent affected

22. Pedigree of Autosomal Dominant Inheritance

23. Noonan syndrome: education • Hypotonia contributes to gross motor delays in childhood • Most are mainstreamed (25% have learning disabilities), verbal performance lower than nonverbal • Hearing loss common • Mild mental retardation 30% • Self esteem is usually comparable to age related peers • Sometimes depression, anxiety

24. Noonan syndrome malignancy • Genes responsible for this condition part of the RAS/MAPK pathway • Juvenile myelomonocytic leukemia (JMML); individuals with PTPN11 have predisposition to this unusual childhood leukemia

25. Turner Syndrome • Incidence 1/2000-5000 • Karyotype 45,X (50%) high rate of spontaneous miscarriage • Other 50% associated with mosaicism (can be with Y) or an abnormal X chromosome • 70-80% result from sperm lacking sex chromosome • Usually sporadic • Xq chromosome necessary for ovarian maintenance and female fertility, Xp responsible for short stature

26. Turner Syndrome

27. Turner Syndrome (Common presentations) • Newborn infant with lymphedema of hands and feet, low posterior hairline • 16 y/o female presents with amenorrhea and short stature, absent of secondary sexual characteristics, ovarian dysgenesis

28. Turner Syndrome • Features: Cystic hygroma, lymphedema, webbed neck, low posterior hairline • Cardiac 50% biscuspid aortic valve, coarctation of the aorta • Other: Renal abnormalities (60%), short stature, broad chest, ovarian dysgenesis • Most are of normal intelligence, some may have learning disabilities particularly spatial perception • Treat GH therapy (gain 6-10 cm height) followed by female hormone replacement

29. Turner Syndrome • May have impaired social adjustment, hyperactivity, anxiety, depression • Some may have chronic health issues including diabetes mellitus type 1 and 2, thyroiditis, osteoporosis • Increased risk of intestinal disorders: IBD, celiac, intestinal telangiectasia (malformation of the blood vessels) • Increased risk of hypertension, atherosclerosis and ischemic heart disease (estrogen effect?)

30. Neurofibromatosis I • One of the most common Autosomal dominant inherited conditions • Also known as Von Recklinghausen Disease • Incidence 1/3000 with 50% de novo mutations (50% with first degree relative affected) • NF1 on chromosome 17 • Diagnosis is based on clinical features • Wide range of clinical severity among patients

31. Neurofibromatosis I (NF1) Consensus diagnostic criteria • Need at least 2: • 6 or more café au lait macules (at least 5 mm before puberty and 15 mm after) • Axillary or groin freckling • 2 or more neurofibromas • Lisch nodules (iris hamartomas) • Optic glioma • Osseous lesions (sphenoid or tibial dysplasia) • Positive family history

32. Children and NF1 • Only 50% affected children with no family history meet criteria by age 1 • Almost 100% will by age 8 • Café au lait macules usually present at birth and increase in number • Other features, axillary freckling, Lisch nodules, appear later in childhood

33. Diagnosis in young children • Diagnostic criteria are usually unequivocal in all but the youngest children • If child have family history only one diagnostic criteria are needed • Gene sequencing can be used in those that do not yet meet diagnostic criteria yet in the absence of family history

34. NF1 clinical findings

35. Medical Problems NF1 • Complications can involve multiple body systems • Central Nervous System: symptomatic optic gliomas usually present before age 6 (proptosis or loss of visual acuity) usually slowly progressive, some spontaneous regress; treatment surgical or chemotherapy • Other brain tumors: brain stem and cerebellar astrocytomas • Headache, seizures, vasculopathy • Learning disabilities in 50%; attention deficits

36. Optic Glioma Eye (2004) 18, N. R Miller

37. Medical Problems NF1 • Musculoskeletal: dystrophic scoliosis requires surgical management • Cardiovascular: Vasculopathy, hypertension, pulmonic stenosis • Neoplasia: Malignant peripheral nerve sheath tumors (neurofibrosarcomas); rapidly growing often painful neurofibroma can occur in adolescence and adults (10%) • Rarely leukemia (CML)

38. Neurofibromas • Discrete cutaneous or subcutaneous lesions can be removed surgically; peripheral nerve sheath tumors • Surgery can be complicated by bleeding and return of growth after procedure • CO2 laser (scarring) • Can be severely disfiguring affecting quality of life; most distressing aspect of the disease for most individuals

39. Neurofibroma:Dermal vs. Plexiform

40. Plexiform Neurofibroma • Surgical treatment of of plexiform neurofibromas often unsatisfactory (develop in 50%) • Radiotherapy contraindicated risk of inducing malignant peripheral nerve sheath tumor • Pirfenidone in phase II clinical trials (antifibrotic agent)

41. Neuroimaging NF1 • Controversy exists regarding the use of routine MRI scanning of the brain in asymptomatic individuals • Most proponents usefulness in finding complications before they become clinically evident • Those against; nonspecific findings and clinical management based on symptoms, regularly repeated MRIs add to cost and patient family anxiety

42. Microdeletion disorders22q11 deletion syndrome • Also known as velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS) • Incidence 1/4000 • Old acronym CATCH 22 : cardiac, abnormal facies, thymic hypoplasia, clefts, hypoparathyroidism (low Ca) • From haploinsufficiency of genes (deletion) at 22q11.2 detected by array CGH or FISH • Increased risk of psychiatric disorders in adolescents and adults

43. Background • VCFS originally described in 1978 by Dr. Robert Shprintzen emphasis on facial dysmorphology • DGS identified earlier in 1965 with predominant T cell deficiency and heart defects • Inherited as AD disorder from interstitial deletions of chromosome 22q11/ 93% sporadic

44. Major clinical characteristics/phenotypes • cardiac malformation (74%) especially conotruncal defects,TOF, IAA, VSD • Palate abnormalities (83%) cleft to VPI, immune deficiency(mostly T-cell), parathyroid deficiency with hypocalcemia • Typical facies: hypoplastic nasal alae bulbous tip and prominent root,long face, narrow paprebral fissures, small cupped ears, long slender fingers • Other features tortuous vessels,growth retardation,urinary anomalies, autoimmune disorders

45. 22q11 Deletion Syndrome

46. 22q11 deletion

47. FISH diagnosis of 22q11

48. 22q11 DS • hypotonia with developmental delays common in infants and children • Learning disabilities common school age children with predominance of nonverbal LD • Schizophrenia (~15-20%), bipolar, anxiety in adolescents and adults • Brain malformation can be present in some including polymicrogyria

49. Polymicrogyria

50. Skeletal Dysplasia Achondroplasia • Autosomal Dominant FGFR3 mutation • Most common cause of dwarfism, 1/15,0000 • Most cases (90%) are a cause of a de novo mutation • Increased risk with advanced paternal age (>35) • Frontal bossing, macrocephaly, trident hands, lumbar lordosis, bowing of legs, rhizomelic shortening of limbs