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Common Genetic Syndromes and their Medical Consequences

Common Genetic Syndromes and their Medical Consequences . Nicole P. Safina MD, FAAP, FACMG Assistant Professor of Pediatrics and Genetics. Common Genetic Syndromes. Review Diagnosis Prognosis Genetics of Syndrome Medical Complications Impact on patient/family.

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Common Genetic Syndromes and their Medical Consequences

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  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

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