Common Genetic Syndromes and their Medical Consequences

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Common Genetic Syndromes and their Medical Consequences Powered By Docstoc
					  Common Genetic
 Syndromes and their
Medical Consequences
  Nicole P. Safina MD, FAAP,
 Assistant Professor of Pediatrics
           and Genetics
     Common Genetic Syndromes
   Review
   Diagnosis
   Prognosis
   Genetics of Syndrome
   Medical Complications
   Impact on patient/family
         Incidence of Common
   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
               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
             Trisomy 21

                   Robertsonian translocation
47, XX,+21         46, XY, rob (14;21), +21
Down Syndrome phenotype
Down Syndrome
     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
Down syndrome Intestinal
               Duodenal atresia,
                esophageal atresia
               Usually present
                with bilious
                vomiting in the
                newborn period,
                double bubble sign
C1-C2 instability/dislocation

laxity of the transverse ligament (13-14% instability)
         Developmental delay
          obvious after first year
         IQ 20-85; Significant
          variability among children
         Early infant toddler
         Most children require
          special education, some
          can be mainstreamed
         Down Syndrome (older
          childhood-teenager )
   Increased risk of sleep apnea (mid face
    hypoplasia, adenoid hypertrophy)
   Celiac disease
   Large adenoids sleep apnea, airway
   Hypothyroidism
   Early adulthood: obesity, insulin resistance,
    premature cardiovascular disease
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
                          Cortical atrophy,
                           ventricular dilation,
                           neurofibrillar tangles
Increased   risk of      AD affects Down
testicular cancer          Syndrome patients at an
                           earlier age than general
           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
            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
   NOT the „male Turners syndrome‟
   Affect male and females equally
      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
   Congenital heart defect , hypertrophic
   Developmental delay of variable degree, hypotonia
   Increased incidence of malignancy
Noonan syndrome
Noonan Syndrome
           Pulmonic stenosis
            often diagnosed in
            infancy (20-50%)
           Cardiomyopathy (20-
            30%) may present at
            birth or develop in
           Lymphatic dysplasia
            and cystic hygroma
            can be present
           Coagulation
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
Noonan: Inheritance
             Autosomal dominant
              30-75% will have an
              affected parent
             PTPN11 (50%)
             SOS1 (16-20%), RAF1
             KRAS <5%
             SHOC2, NRAS <5%
             Clinical diagnosis
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
Pedigree of Autosomal Dominant
     Noonan syndrome: education
   Hypotonia contributes to gross motor delays in
   Most are mainstreamed (25% have learning
    disabilities), verbal performance lower than
   Hearing loss common
   Mild mental retardation 30%
   Self esteem is usually comparable to age related
   Sometimes depression, anxiety
    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
              Turner Syndrome
   Incidence 1/2000-5000
   Karyotype 45,X (50%) high rate of spontaneous
   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
Turner Syndrome
     Turner Syndrome (Common
   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
               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
              Turner Syndrome
   May have impaired social adjustment,
    hyperactivity, anxiety, depression
   Some may have chronic health issues including
    diabetes mellitus type 1 and 2, thyroiditis,
   Increased risk of intestinal disorders: IBD, celiac,
    intestinal telangiectasia (malformation of the blood
   Increased risk of hypertension, atherosclerosis and
    ischemic heart disease (estrogen effect?)
            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
      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
             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
      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
NF1 clinical findings
          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
   Other brain tumors: brain stem and cerebellar
   Headache, seizures, vasculopathy
   Learning disabilities in 50%; attention deficits
Optic Glioma

       Eye (2004) 18, N. R Miller
         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)
   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
Neurofibroma:Dermal vs.
        Plexiform Neurofibroma
   Surgical treatment of of plexiform
    neurofibromas often unsatisfactory (develop
    in 50%)
   Radiotherapy contraindicated risk of
    inducing malignant peripheral nerve sheath
   Pirfenidone in phase II clinical trials
    (antifibrotic agent)
             Neuroimaging NF1
   Controversy exists regarding the use of routine
    MRI scanning of the brain in asymptomatic
   Most proponents usefulness in finding
    complications before they become clinically
   Those against; nonspecific findings and clinical
    management based on symptoms, regularly
    repeated MRIs add to cost and patient family
        Microdeletion disorders
        22q11 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
   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
             Major clinical
   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
22q11 Deletion Syndrome
22q11 deletion
FISH diagnosis of 22q11
                   22q11 DS
   hypotonia with developmental delays
    common in infants and children
   Learning disabilities common school age
    children with predominance of nonverbal
   Schizophrenia (~15-20%), bipolar, anxiety in
    adolescents and adults
   Brain malformation can be present in some
    including polymicrogyria
            Skeletal Dysplasia
   Autosomal Dominant FGFR3 mutation
   Most common cause of dwarfism, 1/15,0000
   Most cases (90%) are a cause of a de novo
   Increased risk with advanced paternal age
   Frontal bossing, macrocephaly, trident
    hands, lumbar lordosis, bowing of legs,
    rhizomelic shortening of limbs
   At risk for hydrocephalus (narrowing of
    jugular foramina), brain stem compression
    at the craniocervical junction 10% (from
    narrowing of foramen magnum) during
    infancy; treatment decompression
   Most are of normal intelligence, although
    will have delayed motor development
    (hypotonia, hyperextensible joints)
MRI achondroplasia
    Achondroplasia chronic issues
   Mid face hypoplasia, dental crowding,
    adenoidal hypertrophy contribute to sleep
   Obesity, lumbar spinal stenosis from
    exaggerated lumbar lordosis
   Genu varum
   Issues with social adjustment
Spinal stenosis
Fragile X Syndrome (Martin-Bell)
   Most common cause of inherited mental
    retardation in males
   Affects 1/3600 males, females ½ male incidence~
   Due trinucleotide expansion disorder (sequence of
    3 base pairs) in FMR1 gene (Xq27.3) CGG
   FMR1 gene expressed abundantly in neurons
   Normal is 5 to 40 repeats
   >58 repeats to 200 premutation carrier
   >200 fragile X mutation, turns off gene, decrease
    FMR protein (hypermethylation)
Fragile X location: Xq27.3
                  Fragile X
   Premutation females: premature ovarian
   Premutation males: Fragile X tremor ataxia
    (late onset cerebellar ataxia, intension
    tremor, memory loss, dementia); females
    occasionally affected
   Premutation may expand to full mutation
    only in female meiotic divisions (increased
    risk based on length of repeat)
Fragile X
X-linked dominant
                       Fragile X
   Moderate mental retardation in males; most have
    normal lifespan
   High rate of behavioral abnormalities: autism,
    hyperactivity, hypersensitivity, poor eye contact
   Females mild mental retardation to LD (depends on X-
    activation pattern)
   seizures
   Connective tissue abnormalities: hyperextensibility, flat
    feet, mitral valve prolapse
   Potential for multiple affected in family tree
 Genetests

 Down syndrome