Common Genetic Common Genetic Syndromes and Syndromes and their Medical their Medical Consequences Consequences
Jan 17, 2016
Common Genetic Common Genetic Syndromes and Syndromes and their Medical their Medical
Consequences Consequences
Common Genetic Common Genetic SyndromesSyndromes
Review Review DiagnosisDiagnosis PrognosisPrognosis Genetics of SyndromeGenetics of Syndrome Medical ComplicationsMedical Complications Impact on patient/familyImpact on patient/family
Incidence of Common Incidence of Common SyndromesSyndromes
Down Syndrome 1/700Down Syndrome 1/700 Noonan Syndrome 1/1000-3000Noonan Syndrome 1/1000-3000 Turner Syndrome 1/5000Turner Syndrome 1/5000 Neurofibromatosis I 1/3000Neurofibromatosis I 1/3000 22q11 Deletion 1/400022q11 Deletion 1/4000 Achondroplasia 1/ 15,000-40,000Achondroplasia 1/ 15,000-40,000 Fragile X 1/3600 males, 1/6000 Fragile X 1/3600 males, 1/6000
femalesfemales
Down SyndromeDown Syndrome 1/650-700 births most common 1/650-700 births most common
aneuploidy; most common cause of aneuploidy; most common cause of genetic MRgenetic MR
Langdon Down in 1866; 1959 the Langdon Down in 1866; 1959 the chromosome cause became clearchromosome cause became clear
Etiology: maternal nondisjunction (90%) Etiology: maternal nondisjunction (90%) rarely paternal nondisjunction; rarely paternal nondisjunction; chromosome translocation (5%), mosaic chromosome translocation (5%), mosaic (<5%)(<5%)
Increase risk with increase maternal age Increase risk with increase maternal age or parent is a translocation carrieror parent is a translocation carrier
Risk of reoccurrence typically depends Risk of reoccurrence typically depends on mother’s age for full trisomyon mother’s age for full trisomy
Trisomy 21Trisomy 21
Robertsonian translocation46, XY, rob (14;21), +2147, XX,+21
Down Syndrome Down Syndrome phenotypephenotype
Down SyndromeDown Syndrome
Down Syndrome infant-Down Syndrome infant-childchild
85% survive to 1 year and 50% live >age 5085% survive to 1 year and 50% live >age 50 30-50% CHD with endocardial cushion 30-50% CHD with endocardial cushion
defects most common (Atrioventicular defects most common (Atrioventicular canal)canal)
Gastroesopageal reflux, otitis media, mixed Gastroesopageal reflux, otitis media, mixed hearing losshearing loss
Ophthalmologic abnormalities: strabismus, Ophthalmologic abnormalities: strabismus, cataracts glaucomacataracts glaucoma
Increased risk of leukemia (10-50 times)Increased risk of leukemia (10-50 times) Hypothyroidism (30%)Hypothyroidism (30%) Hirschsprung disease Hirschsprung disease Increased risk for epilepsyIncreased risk for epilepsy
Down syndrome Down syndrome Intestinal AtresiasIntestinal Atresias
Duodenal Duodenal atresia, atresia, esophageal esophageal atresiaatresia
Usually present Usually present with bilious with bilious vomiting in the vomiting in the newborn period, newborn period, double bubble double bubble signsign
C1-C2 C1-C2 instability/dislocationinstability/dislocation
laxity of the transverse ligament (13-14% instability)
C1
DevelopmentDevelopment Developmental delay Developmental delay
obvious after first obvious after first yearyear
IQ 20-85; Significant IQ 20-85; Significant variability among variability among childrenchildren
Early infant toddler Early infant toddler connectionconnection
Most children Most children require special require special education, some can education, some can be mainstreamedbe mainstreamed
Down Syndrome (older Down Syndrome (older childhood-teenager )childhood-teenager )
Increased risk of sleep apnea (mid Increased risk of sleep apnea (mid face hypoplasia, adenoid hypertrophy)face hypoplasia, adenoid hypertrophy)
Celiac diseaseCeliac disease Large adenoids sleep apnea, airway Large adenoids sleep apnea, airway
obstructionobstruction HypothyroidismHypothyroidism Early adulthood: obesity, insulin Early adulthood: obesity, insulin
resistance, premature cardiovascular resistance, premature cardiovascular diseasedisease
Aging and Down Aging and Down SyndromeSyndrome
Premature senility Premature senility associated with associated with characteristics of characteristics of Alzheimer disease (AD)Alzheimer disease (AD)
Up to 10-25% show Up to 10-25% show signs of AD before age signs of AD before age 50 and up to 50% 50 and up to 50% before the 6before the 6thth decade decade
Cortical atrophy, Cortical atrophy, ventricular dilation, ventricular dilation, neurofibrillar tanglesneurofibrillar tangles
AD affects Down AD affects Down Syndrome patients at Syndrome patients at an earlier age than an earlier age than general populationgeneral population
Increased risk Increased risk of testicular of testicular cancercancer
Society and CultureSociety and Culture Acceptance in family dynamic and Acceptance in family dynamic and
society can impact overall society can impact overall development (parenting , support development (parenting , support groups)groups)
Starts in prenatal settingStarts in prenatal setting Education, housing and work Education, housing and work
environmentsenvironments Medical professionals play a major Medical professionals play a major
role to help shaping public attitudesrole to help shaping public attitudes National Association of Down National Association of Down
Syndrome[1960]Syndrome[1960]
Noonan syndromeNoonan syndrome
One of the most common genetic One of the most common genetic disorders with congenital heart disorders with congenital heart defect (1/3000)defect (1/3000)
Wide range of clinical variability Wide range of clinical variability and phenotype expressionand phenotype expression
Autosomal dominant with normal Autosomal dominant with normal chromosomeschromosomes
NOT the ‘male Turners syndrome’NOT the ‘male Turners syndrome’ Affect male and females equallyAffect male and females equally
Noonan syndrome: Noonan syndrome: featuresfeatures
Broad, short or webbed neckBroad, short or webbed neck Unusual chest shape with superior pectus Unusual chest shape with superior pectus
carinatum, inferior pectus excavatumcarinatum, inferior pectus excavatum Apparently wide low-set nipplesApparently wide low-set nipples Cryptorchidism in males Cryptorchidism in males Down slanting palpebral fissures, ptosis, Down slanting palpebral fissures, ptosis,
low set earslow set ears Congenital heart defect , hypertrophic Congenital heart defect , hypertrophic
cardiomyopathycardiomyopathy Developmental delay of variable degree, Developmental delay of variable degree,
hypotoniahypotonia Increased incidence of malignancyIncreased incidence of malignancy
Noonan syndromeNoonan syndrome
Noonan SyndromeNoonan Syndrome
Pulmonic stenosis Pulmonic stenosis often diagnosed in often diagnosed in infancy (20-50%)infancy (20-50%)
Cardiomyopathy Cardiomyopathy (20-30%) may (20-30%) may present at birth or present at birth or develop in develop in childhoodchildhood
Lymphatic dysplasia Lymphatic dysplasia and cystic hygroma and cystic hygroma can be presentcan be present
Coagulation Coagulation abnormalitiesabnormalities
Noonan syndromeNoonan syndrome Diagnosis can be Diagnosis can be
missed if features are missed if features are subtlesubtle
Failure to thrive with Failure to thrive with GE reflux present in GE reflux present in infancy; FTT self infancy; FTT self limitedlimited
Short stature late Short stature late childhood adolescence childhood adolescence sometimes with growth sometimes with growth hormone deficiency; hormone deficiency; mean female ht 150 mean female ht 150 females, 160 malesfemales, 160 males
Noonan: InheritanceNoonan: Inheritance
Autosomal Autosomal dominant 30-75% dominant 30-75% will have an will have an affected parentaffected parent
PTPN11 (50%)PTPN11 (50%) SOS1 (16-20%), SOS1 (16-20%),
RAF1 (3-17%)RAF1 (3-17%) KRAS <5%KRAS <5% SHOC2, NRAS <5%SHOC2, NRAS <5% Clinical diagnosisClinical diagnosis
Autosomal Dominant Autosomal Dominant InheritanceInheritance
Affects males and females Affects males and females equallyequally
““Vertical” transmission (one Vertical” transmission (one generation to the next)generation to the next)
High spontaneous mutation rateHigh spontaneous mutation rate 50% reoccurrence risk for 50% reoccurrence risk for
affected child when parent affected child when parent affectedaffected
Pedigree of Autosomal Pedigree of Autosomal Dominant InheritanceDominant Inheritance
Noonan syndrome: Noonan syndrome: educationeducation
Hypotonia contributes to gross motor Hypotonia contributes to gross motor delays in childhooddelays in childhood
Most are mainstreamed (25% have Most are mainstreamed (25% have learning disabilities), verbal learning disabilities), verbal performance lower than nonverbalperformance lower than nonverbal
Hearing loss commonHearing loss common Mild mental retardation 30%Mild mental retardation 30% Self esteem is usually comparable to Self esteem is usually comparable to
age related peersage related peers Sometimes depression, anxietySometimes depression, anxiety
Noonan syndrome Noonan syndrome malignancymalignancy
Genes responsible for this Genes responsible for this condition part of the RAS/MAPK condition part of the RAS/MAPK pathwaypathway
Juvenile myelomonocytic Juvenile myelomonocytic leukemia (JMML); individuals leukemia (JMML); individuals with PTPN11 have predisposition with PTPN11 have predisposition to this unusual childhood to this unusual childhood leukemialeukemia
Turner SyndromeTurner Syndrome Incidence 1/2000-5000Incidence 1/2000-5000 Karyotype 45,X (50%) high rate of Karyotype 45,X (50%) high rate of
spontaneous miscarriagespontaneous miscarriage Other 50% associated with mosaicism (can Other 50% associated with mosaicism (can
be with Y) or an abnormal X chromosome be with Y) or an abnormal X chromosome 70-80% result from sperm lacking sex 70-80% result from sperm lacking sex
chromosomechromosome Usually sporadic Usually sporadic Xq chromosome necessary for ovarian Xq chromosome necessary for ovarian
maintenance and female fertility, Xp maintenance and female fertility, Xp responsible for short statureresponsible for short stature
Turner SyndromeTurner Syndrome
Turner Syndrome Turner Syndrome (Common presentations)(Common presentations)
Newborn infant with Newborn infant with lymphedema of hands and feet, lymphedema of hands and feet, low posterior hairlinelow posterior hairline
16 y/o female presents with 16 y/o female presents with amenorrhea and short stature, amenorrhea and short stature, absent of secondary sexual absent of secondary sexual characteristics, ovarian characteristics, ovarian dysgenesisdysgenesis
Turner SyndromeTurner Syndrome Features: Cystic hygroma, lymphedema, Features: Cystic hygroma, lymphedema,
webbed neck, low posterior hairlinewebbed neck, low posterior hairline Cardiac 50% biscuspid aortic valve, Cardiac 50% biscuspid aortic valve,
coarctation of the aortacoarctation of the aorta Other: Renal abnormalities (60%), short Other: Renal abnormalities (60%), short
stature, broad chest, ovarian dysgenesisstature, broad chest, ovarian dysgenesis Most are of normal intelligence, some Most are of normal intelligence, some
may have learning disabilities may have learning disabilities particularly spatial perceptionparticularly spatial perception
Treat GH therapy (gain 6-10 cm height) Treat GH therapy (gain 6-10 cm height) followed by female hormone replacementfollowed by female hormone replacement
Turner SyndromeTurner Syndrome May have impaired social adjustment, May have impaired social adjustment,
hyperactivity, anxiety, depressionhyperactivity, anxiety, depression Some may have chronic health issues Some may have chronic health issues
including diabetes mellitus type 1 and including diabetes mellitus type 1 and 2, thyroiditis, osteoporosis2, thyroiditis, osteoporosis
Increased risk of intestinal disorders: Increased risk of intestinal disorders: IBD, celiac, intestinal telangiectasia IBD, celiac, intestinal telangiectasia (malformation of the blood vessels)(malformation of the blood vessels)
Increased risk of hypertension, Increased risk of hypertension, atherosclerosis and ischemic heart atherosclerosis and ischemic heart disease (estrogen effect?)disease (estrogen effect?)
Neurofibromatosis INeurofibromatosis I
One of the most common Autosomal One of the most common Autosomal dominant inherited conditionsdominant inherited conditions
Also known as Von Recklinghausen Also known as Von Recklinghausen DiseaseDisease
Incidence 1/3000 with 50% de novo Incidence 1/3000 with 50% de novo mutations (50% with first degree relative mutations (50% with first degree relative affected)affected)
NF1 on chromosome 17NF1 on chromosome 17 Diagnosis is based on clinical featuresDiagnosis is based on clinical features Wide range of clinical severity among Wide range of clinical severity among
patientspatients
Neurofibromatosis I Neurofibromatosis I (NF1) Consensus (NF1) Consensus
diagnostic criteria diagnostic criteria Need at least 2Need at least 2:: 6 or more café au lait macules (at least 6 or more café au lait macules (at least
5 mm before puberty and 15 mm after)5 mm before puberty and 15 mm after) Axillary or groin frecklingAxillary or groin freckling 2 or more neurofibromas2 or more neurofibromas Lisch nodules (iris hamartomas)Lisch nodules (iris hamartomas) Optic gliomaOptic glioma Osseous lesions (sphenoid or tibial Osseous lesions (sphenoid or tibial
dysplasia)dysplasia) Positive family history Positive family history
Children and NF1Children and NF1
Only 50% affected children with no Only 50% affected children with no family history meet criteria by age 1family history meet criteria by age 1
Almost 100% will by age 8Almost 100% will by age 8 Café au lait macules usually present Café au lait macules usually present
at birth and increase in numberat birth and increase in number Other features, axillary freckling, Other features, axillary freckling,
Lisch nodules, appear later in Lisch nodules, appear later in childhoodchildhood
Diagnosis in young Diagnosis in young childrenchildren
Diagnostic criteria are usually Diagnostic criteria are usually unequivocal in all but the unequivocal in all but the youngest childrenyoungest children
If child have family history only If child have family history only one diagnostic criteria are neededone diagnostic criteria are needed
Gene sequencing can be used in Gene sequencing can be used in those that do not yet meet those that do not yet meet diagnostic criteria yet in the diagnostic criteria yet in the absence of family historyabsence of family history
NF1 clinical findingsNF1 clinical findings
Medical Problems NF1Medical Problems NF1 Complications can involve multiple body Complications can involve multiple body
systemssystems Central Nervous SystemCentral Nervous System: symptomatic optic : symptomatic optic
gliomas usually present before age 6 gliomas usually present before age 6 (proptosis or loss of visual acuity) usually (proptosis or loss of visual acuity) usually slowly progressive, some spontaneous slowly progressive, some spontaneous regress; treatment surgical or chemotherapyregress; treatment surgical or chemotherapy
Other brain tumors: brain stem and Other brain tumors: brain stem and cerebellar astrocytomascerebellar astrocytomas
Headache, seizures, vasculopathyHeadache, seizures, vasculopathy Learning disabilities in 50%; attention Learning disabilities in 50%; attention
deficitsdeficits
Optic GliomaOptic Glioma
Eye (2004) 18, N. R Miller
Medical Problems NF1Medical Problems NF1 Musculoskeletal: dystrophic scoliosis Musculoskeletal: dystrophic scoliosis
requires surgical managementrequires surgical management Cardiovascular: Vasculopathy, Cardiovascular: Vasculopathy,
hypertension, pulmonic stenosishypertension, pulmonic stenosis Neoplasia: Malignant peripheral Neoplasia: Malignant peripheral
nerve sheath tumors nerve sheath tumors (neurofibrosarcomas); rapidly (neurofibrosarcomas); rapidly growing often painful neurofibroma growing often painful neurofibroma can occur in adolescence and adults can occur in adolescence and adults (10%)(10%)
Rarely leukemia (CML)Rarely leukemia (CML)
NeurofibromasNeurofibromas Discrete cutaneous or subcutaneous Discrete cutaneous or subcutaneous
lesions can be removed surgically; lesions can be removed surgically; peripheral nerve sheath tumorsperipheral nerve sheath tumors
Surgery can be complicated by Surgery can be complicated by bleeding and return of growth after bleeding and return of growth after procedureprocedure
CO2 laser (scarring)CO2 laser (scarring) Can be severely disfiguring affecting Can be severely disfiguring affecting
quality of life; most distressing quality of life; most distressing aspect of the disease for most aspect of the disease for most individualsindividuals
Neurofibroma:Dermal vs. Neurofibroma:Dermal vs. PlexiformPlexiform
Plexiform NeurofibromaPlexiform Neurofibroma
Surgical treatment of of Surgical treatment of of plexiform neurofibromas often plexiform neurofibromas often unsatisfactory (develop in 50%)unsatisfactory (develop in 50%)
Radiotherapy contraindicated Radiotherapy contraindicated risk of inducing malignant risk of inducing malignant peripheral nerve sheath tumorperipheral nerve sheath tumor
Pirfenidone in phase II clinical Pirfenidone in phase II clinical trials (antifibrotic agent)trials (antifibrotic agent)
Neuroimaging NF1Neuroimaging NF1 Controversy exists regarding the use Controversy exists regarding the use
of routine MRI scanning of the brain of routine MRI scanning of the brain in asymptomatic individualsin asymptomatic individuals
Most proponents usefulness in finding Most proponents usefulness in finding complications before they become complications before they become clinically evidentclinically evident
Those against; nonspecific findings Those against; nonspecific findings and clinical management based on and clinical management based on symptoms, regularly repeated MRIs symptoms, regularly repeated MRIs add to cost and patient family anxietyadd to cost and patient family anxiety
Microdeletion disordersMicrodeletion disorders22q11 deletion syndrome22q11 deletion syndrome Also known as velocardiofacial syndrome Also known as velocardiofacial syndrome
(VCFS), DiGeorge syndrome (DGS)(VCFS), DiGeorge syndrome (DGS) Incidence 1/4000Incidence 1/4000 Old acronym CATCH 22 : cardiac, Old acronym CATCH 22 : cardiac,
abnormal facies, thymic hypoplasia, abnormal facies, thymic hypoplasia, clefts, hypoparathyroidism (low Ca)clefts, hypoparathyroidism (low Ca)
From haploinsufficiency of genes From haploinsufficiency of genes (deletion) at 22q11.2 detected by array (deletion) at 22q11.2 detected by array CGH or FISHCGH or FISH
Increased risk of psychiatric disorders in Increased risk of psychiatric disorders in adolescents and adultsadolescents and adults
BackgroundBackground VCFS originally described in 1978 VCFS originally described in 1978
by Dr. Robert Shprintzen emphasis by Dr. Robert Shprintzen emphasis on facial dysmorphologyon facial dysmorphology
DGS identified earlier in 1965 with DGS identified earlier in 1965 with predominant T cell deficiency and predominant T cell deficiency and heart defectsheart defects
Inherited as AD disorder from Inherited as AD disorder from interstitial deletions of chromosome interstitial deletions of chromosome 22q11/ 93% sporadic 22q11/ 93% sporadic
Major clinical Major clinical characteristics/phenotypcharacteristics/phenotyp
eses cardiac malformation (74%) especially cardiac malformation (74%) especially conotruncal defects,TOF, IAA, VSDconotruncal defects,TOF, IAA, VSD
Palate abnormalities (83%) cleft to VPI, Palate abnormalities (83%) cleft to VPI, immune deficiency(mostly T-cell), immune deficiency(mostly T-cell), parathyroid deficiency with hypocalcemiaparathyroid deficiency with hypocalcemia
Typical facies: hypoplastic nasal alae Typical facies: hypoplastic nasal alae bulbous tip and prominent root,long face, bulbous tip and prominent root,long face, narrow paprebral fissures, small cupped narrow paprebral fissures, small cupped ears, long slender fingersears, long slender fingers
Other features tortuous vessels,growth Other features tortuous vessels,growth retardation,urinary anomalies, retardation,urinary anomalies, autoimmune disordersautoimmune disorders
22q11 Deletion 22q11 Deletion SyndromeSyndrome
22q11 deletion22q11 deletion
FISH diagnosis of 22q11FISH diagnosis of 22q11
22q11 DS22q11 DS
hypotonia with developmental hypotonia with developmental delays common in infants and delays common in infants and childrenchildren
Learning disabilities common Learning disabilities common school age children with school age children with predominance of nonverbal LDpredominance of nonverbal LD
Schizophrenia (~15-20%), bipolar, Schizophrenia (~15-20%), bipolar, anxiety in adolescents and adultsanxiety in adolescents and adults
Brain malformation can be present Brain malformation can be present in some including polymicrogyriain some including polymicrogyria
PolymicrogyriaPolymicrogyria
Skeletal Dysplasia Skeletal Dysplasia AchondroplasiaAchondroplasia
Autosomal Dominant FGFR3 mutationAutosomal Dominant FGFR3 mutation Most common cause of dwarfism, Most common cause of dwarfism,
1/15,00001/15,0000 Most cases (90%) are a cause of a de Most cases (90%) are a cause of a de
novo mutationnovo mutation Increased risk with advanced paternal Increased risk with advanced paternal
age (>35)age (>35) Frontal bossing, macrocephaly, Frontal bossing, macrocephaly,
trident hands, lumbar lordosis, trident hands, lumbar lordosis, bowing of legs, rhizomelic shortening bowing of legs, rhizomelic shortening of limbsof limbs
AchondroplasiaAchondroplasia
AchondroplasiaAchondroplasia
At risk for hydrocephalus (narrowing At risk for hydrocephalus (narrowing of jugular foramina), brain stem of jugular foramina), brain stem compression at the craniocervical compression at the craniocervical junction 10% (from narrowing of junction 10% (from narrowing of foramen magnum) during infancy; foramen magnum) during infancy; treatment decompressiontreatment decompression
Most are of normal intelligence, Most are of normal intelligence, although will have delayed motor although will have delayed motor development (hypotonia, development (hypotonia, hyperextensible joints)hyperextensible joints)
MRI achondroplasiaMRI achondroplasia
Achondroplasia chronic Achondroplasia chronic issuesissues
Mid face hypoplasia, dental Mid face hypoplasia, dental crowding, adenoidal hypertrophy crowding, adenoidal hypertrophy contribute to sleep apneacontribute to sleep apnea
Obesity, lumbar spinal stenosis Obesity, lumbar spinal stenosis from exaggerated lumbar from exaggerated lumbar lordosislordosis
Genu varumGenu varum Issues with social adjustmentIssues with social adjustment
Spinal stenosisSpinal stenosis
Fragile X Syndrome Fragile X Syndrome (Martin-Bell)(Martin-Bell)
Most common cause of inherited mental Most common cause of inherited mental retardation in malesretardation in males
Affects 1/3600 males, females ½ male Affects 1/3600 males, females ½ male incidence~ 1/6000incidence~ 1/6000
Due trinucleotide expansion disorder Due trinucleotide expansion disorder (sequence of 3 base pairs) in FMR1 gene (sequence of 3 base pairs) in FMR1 gene (Xq27.3) CGG(Xq27.3) CGG
FMR1 gene expressed abundantly in FMR1 gene expressed abundantly in neuronsneurons
Normal is 5 to 40 repeatsNormal is 5 to 40 repeats >58 repeats to 200 premutation carrier>58 repeats to 200 premutation carrier >200 fragile X mutation, turns off gene, >200 fragile X mutation, turns off gene,
decrease FMR protein (hypermethylation)decrease FMR protein (hypermethylation)
Fragile X location: Fragile X location: Xq27.3Xq27.3
Fragile XFragile X Premutation females: premature Premutation females: premature
ovarian failureovarian failure Premutation males: Fragile X tremor Premutation males: Fragile X tremor
ataxia (late onset cerebellar ataxia, ataxia (late onset cerebellar ataxia, intension tremor, memory loss, intension tremor, memory loss, dementia); females occasionally dementia); females occasionally affectedaffected
Premutation may expand to full Premutation may expand to full mutation only in female meiotic mutation only in female meiotic divisions (increased risk based on divisions (increased risk based on length of repeat)length of repeat)
Fragile XFragile X
X-linked dominant
Fragile XFragile X Moderate mental retardation in males; most Moderate mental retardation in males; most
have normal lifespanhave normal lifespan High rate of behavioral abnormalities: autism, High rate of behavioral abnormalities: autism,
hyperactivity, hypersensitivity, poor eye hyperactivity, hypersensitivity, poor eye contactcontact
Females mild mental retardation to LD Females mild mental retardation to LD (depends on X-activation pattern)(depends on X-activation pattern)
seizuresseizures Connective tissue abnormalities: Connective tissue abnormalities:
hyperextensibility, flat feet, mitral valve hyperextensibility, flat feet, mitral valve prolapseprolapse
Potential for multiple affected in family treePotential for multiple affected in family tree
ResourcesResources
www.genetests.org www.genetests.org GenetestsGenetests
www.ncbi.nlm.nih.gov/omim www.ncbi.nlm.nih.gov/omim OMIMOMIM
www.dsahr.org Down www.dsahr.org Down syndromesyndrome
Questions?Questions?