The 25 Genetic Syndromes
You Really Should Know
(Some a little more than others…)
Sarah Hall PGY-4
April 2007
The Countdown Begins…
Bardet-Biedl Syndrome

Previously Laurence-Moon-Bardet-Biedl

AR
Obesity
 Postaxial polydactyly
 Hypogonadism
 Mental deficiency

Bardet-Biedl Syndrome

Pigmentary retinopathy



Problems with night
vision, color, visual acuity
Myopia
Kidney – concentrating
problems and RTA
Oculo-Auriculo-Vertebral
Spectrum


Goldenhar Syndrome, Facio-AuriculoVertebral Syndrome
Sporadic inheritance




Hemifacial microsomia
Vetebral anomalies


Abn 1st and 2nd brachial arches
Sporadic (2% recurrence)
Hemivertebrae, butterfly
Normal IQ
Oculo-Auriculo-Vertebral
Spectrum



Microtia,
preauricular tags or
pits, often a line
from tragus to
corner of mouth
Follow for deafness
Line from tragus to
corner of mouth
Oculo-Auriculo-Vertebral
Spectrum


Epibulbar dermoids
Coloboma
Stickler Syndrome






AD
Flat face
Scooped out nasal bridge
U-Shaped cleft palate
Robin sequence
Myopia


Risk of retinal detachment
Hyperextensible joints
Beware Difficult Airway!
CHARGE Syndrome


AD
1/1000


Coloboma
Heart


Need 4/6 features:


Choanal Atresia
Retardation



Tetralogy, aortic arch,
conotruncal defects
Growth and development
Genitourinary
Ear / deafness
CHARGE Syndrome
VATER / VACTERL Association

Association
(anomalies that
occur more often
together than by
chance alone)



Vertebral
Anal atresia
Cardiac



TEF
Renal



1/5,000
Need 3 of 5


VSD
Horseshoe
Ectopic
Limb anomalies

Polydactylyl, forearm
defects, absent thumbs
(clue 2 vessel cord)
Sotos Syndrome

Cerebral Gigantism







AD
1/25,000
LGA
Macrocephaly, frontal prominence
Hypotonia
Seizures
Developmental delay and behavioral
difficulties
Waardenburg Syndrome






AD, PAX-3 mutation
1/15,000 – 1/25,000
Heterochromia
White forelock
SNHL 15 - 25%
Dystropia canthorum

Wide nasal bridge, short
palpebral fissures
Cornelia de Lange Syndrome



AD (most cases sporadic)
1/25,000
Hirsutism







Bushy and arched eyebrows
Long curly eyelashes
Low hairline
Upturned nose and cupid’s
bow lips
Microcephaly, LGA and
postnatal FTT
Ulnar dysplasia
Mental retardation
Beckwith-Wiedemann
Syndrome




AD, 11p15
Macrosomia and
hemihypertrophy
Macroglossia
Hypoglycemia


Abdominal wall defects


Pancreatic islet hyperplasia
Omphalocele
Pits and ear creases
Beckwith Wiedemann
Syndrome

Increased incidence of pediatric tumors
1.
2.
Wilms
Hepatoblastoma
Suggested screening:
 AUS q 3mo until 8y
 AFP q 6w until 4y

Normal IQ
Rubenstein-Taybi Syndrome









AD, microdeletion 16q
1/25,000
Microcephaly
Growth retardation
Down-turned upper lip
Beaked nose
Mental retardation
Broad thumbs and great toes
Increased spinal cord tethering
DiGeorge / VCF Syndromes


1/5,000
AD

Cardiac


C – Cardiac
A – Abnormal facies

T – Thymic hypoplasia
H – Hypocalcemia
22 - 22q11 deletion
Hypocalcemia in 1st
year of life

C – Cleft palate

VSD
Conotruncal abn:
tetralogy, truncus,
interrupted aortic arch
Parathyroid aplasia or
hypoplasia
T cell abnormalities
A Quick Recap…
With this
screen for:
Name two things
associated with:
Treacher Collins Syndrome



AD
Symmetric
downslanting eyes
Abnormal ears


Lower eyelid
colobomas
Zygomatic
hypoplasia
Williams Syndrome





AD
Microdeletion 7q (elastin)
1/15,000
Cocktail personality
Distinctive facies




Long philtrum
Broad mouth
Stellate irises
Short nose with bulbous nasal
tip
Williams Syndrome

Cardiac:



Supravalvular aortic stenosis (80%)
Peripheral pulmonic stenosis
Pulmonary valvular stenosis
Mental retardation
 Idiopathic hypercalcemia

Williams Syndrome

Monitoring:








Cardiology exam at birth and puberty, yearly BP
Serum Ca
Serum creatinine q 4y
Urinalysis – annually, unless N then q 2y
Urine Ca/Cr ratio – q 2y
Baseline US of bladder and kidneys at birth
Thyroid function q 2y, q4y after 5y of age
Hearing and ophtho assessment before 3y
Neurofibromatosis

NF-1




AD
1/3,000; 30 % new mutations in NF-1
NF-1 on chm 17q11
NF-2



AD
1/33,000; 50% new mutations in NF-2
NF-2 on chm 22q1
Neurofibromatosis 1

Dx:

> 6 CALM







> 2 NF / 1 plexiform
Axillary/groin freckling
> 2 Lisch nodules
Optic gliomas
Skeletal abn


> 5 mm pre-pub
> 15 mm post-pub
Cortical thinning of long
bones + pseudoarthrosis,
sphenoid dysplasia
First degree relative

Health Supervision:



Slit lamp exam for
1st degree relatives
at Dx (Lisch n.)
Annual ophtho
exams q 1y
Hearing before
school-entry
Neurofibromatosis 2

Dx:


Bilateral acoustic neuromas (VIII tumors)
First degree relative with NF-2 and 2 of:
Neurofibroma
 Meningioma
 Schwannoma
 Juvenile posterior subcapsular lenticular
opacities

Other Syndromes with CALM

Coast of California =
NF and Tuberous sclerosis

Coast of Maine =
McCune Albright
Achondroplasia

AD






Defect in FGFR-3
1/10,000
Short limb dwarfism
Megalocephaly
Midface hypoplassia
Trident hand
Achondroplasia





Square pelvis
Small sacroiliac notch
Narrowed
interpeduncular
distances
Shortened proximal
long bones
Narrow foramen
magnum

Hydrocephalus
Achondroplasia

Risks







UAW obstruction
Sudden death in
infants
OSA
Hydrocephalus
Cord compression
due to kyphosis
GERD
Obesity

Health supervision:




Document occipital
frontal circumference
& growth parameters
Neuroimaging/Cspine imaging
Hearing assessments
annually from 1y
Polysomnography at
birth and prn
Thanatophoric Dysplasia




Another type of
rhizometric skeletal
dysplasia
Lethal
Small chest –
respiratory distress
Typical findings:



No sciatic notch
French-telephone femurs
H-shaped vertebrae
Marfan Syndrome



AD, FBN1, fibrillin
1/15,000
Major criteria in 2
systems and another
system

Ocular


Upward lens
subluxation
CV



Dilatation of
ascending aorta +
AR
Dissection of
ascending aorta
Minor: MVP
Marfan Syndrome

Major Skeletal (4/8)






Pectus carinatum
Pectus excavatum
needing Sx
Wrist & thumb sign
Decreased U:L ratio,
span-ht ratio > 1.05
Scoliosis > 20o
Decreased elbow
extension < 170o
Marfan Syndrome

Pulmonary



Skin


No major criteria
Minor:
pneumothorax
Lumbosacral dural
ectasia on CT or MRI
FHx

Major: positive




B-blockers may
decrease aortic
dilatation
SBE PPx
No competitive
sports if mild aortic
dilatation
Glaucoma due to
dislocated lens
Homocysteinuria




Marfanoid appearance
Myopia
Downward dislocation
of lens
Arterial
thromboembolism
Prader-Willi Syndrome

Causes




Paternal deletion
15q11 – 13 (75%)
Maternal UPD (20%)
Mutation of
imprinting center
Structural abn in
gene

Hypotonic infants








Often breech delivery
Poor feeding
Insatiable appetite later
Cognitive impairment
Often fair complexion
Almond-shaped eyes
Small hands and feet
Infertile (hypoplastic
testes and penis)
Prader-Willi Syndrome
Diabetes mellitus as adults –
unresponsive to oral hypoglycemics
 Can die of Pickwickian Syndrome
 Rx




Intensive behavioural modification
GH replacement improves body
composition (decreased fat)
Testosterone replacement for boys
Angelman Syndrome

Causes:




Large maternal
deletion (75%)
Paternal UPD (2%)
Imprinting center
mutation (2%)
Mutation in
associated gene
UBE3A (5 – 10%)
Angelman Syndrome







Severe mental
retardation
Paroxysms of laughter
Absent speech
Ataxia and jerky arm
movements (puppet
gait)
Hypopigmentation
Microbrachycephaly,
wide mouth, tongue
protrusion
Seizures
Fetal Alcohol Syndrome

1.
Criteria:
Facial dysmorphism



Smooth philtrum
Thin vermillion
border
Small palpebral
fissures
Fetal Alcohol Syndrome
2.
CNS Abnormalities

Structural




3.



Microcephaly
Abn brain
Neurological
Functional
Global cognitive delay
performance< 3%
Deficits 1 SD below mean
in 3 areas (social, motor
etc)
Growth problems
Ht, wt, or both <
10% at any time



Prenatal
Postnatal
Maternal EtOH
exposure


Confirmed
Unknown
Fetal Alcohol Syndrome

Neurodevelopmental effects



Intelligence: IQ 50 – 115 (normal 100)
Activity and attention: ADHD
Difficulties with
Language and number processing
 Memory and sequencing skills
 Interpersonal skills


Hearing – both CHL and SNHL
Atypical Fetal Alcohol
Syndrome

Used to be called Fetal Alcohol Effects


Then changed to



Describing alcohol exposure with some, not
all, features
Alcohol-Related Birth Defects (ARBD)
Alcohol-Related Neurodevelopmental
Effects (ARND)
Now refer to all as Atypical FAS
How much is too much?

Less than 15 oz/day
has no effect

More than 5 drinks,
more than once per
week = Heavy
Drinking
Klinefelter Syndrome

47 XXY


Non-dysjunction


1/1,000



Dx made at puberty
See axillary and pubic hair
growth with infantile testes
(< 2.5 cm)
Tall, long arms and legs
Gynecomastia
Most common cause
hypogonadism and
infertility in males
Klinefelter Syndrome


Can develop osteopenia
osteoporosis
Behavioral problems



Testosterone
replacement at 11 –
12y

Risk of recurrence:
1 – 2%
ADHD
Difficulties with:




Expressive speech
Auditory processing
Auditory memory
Motor skills
Fragile X Syndrome







1/150
FMR1 gene
Most inheritable form of
mental retardation
Large face
Prominent jaw
Big ears
Macroorchidism after
puberty
Fragile X Syndrome




Length of CGG
trinucleotide repeat
determines disease
5 – 50 repeats = N
52 – 200 = Premutation
(appear normal)
> 200 = Symptomatic

Also see:




IQ 30 - 55
Hyperactivity,
ADHD
Autism
Can see


Hyperextensible
joints
MVP
Another Quick Recap…
Name this
syndrome:
Child will
likely be:
a. Tall
b. Short
Typical personality
with:
Electrolyte abn?
Noonan Syndrome







AD
1/1,000 – 1/2,500
Short or webbed neck
Shield chest, cubitus
valgus
Downslanting palpebral
fissures
Ears low-set, posteriorly
rotated
Low posterior hairline
Noonan Syndrome

Heart:





Pulmonary valve
stenosis
Hypertrophic
cardiomyopathy
(20%)
ASD
Cryptorchidism
Coagulation abn
seen in 1/3

Can look like




NF –1
Cardio-faciocutaneous syndrome
(both have sparse
curly hair)
Costello S
FAS
Turner Syndrome



XO, 15% are mosaic
1/2,000
Short stature and gonadal
dysgenesis




Congenital lymphedema,
edema over fingers and toes
Shield chest, cubitus valgus
Low posterior hairline
Webbed neck
Turner Syndrome

Primary amenorrhea




Renal anomalies


Streak ovaries
Some have menses
Some are fertile
Horseshoe kidney etc
Cardiac


Bicuspid aortic valve, coarctation, valvular aortic
stenosis
Echo q 5y
Turner Syndrome


Normal IQ, but difficulties
with visuo-spatial
orientation
Infants:




Hydrops fetalis
Cystic hygromas
Excessive loose skin around
neck in infants
Rx

Estrogen replacement
Trisomies 13 & 18

Trisomy 13



1/5000
Patau Syndrome
Usually die by 1y

Trisomy 18



3/1000
Edwards Syndrome
Usually die by 1 mo
Trisomies 13 & 18

Trisomy 13




Usually normal bwt
Cleft lip or palate
Coloboma
Polydactyly

Trisomy 18




SGA
Short sternum
Rockerbottom feet
Horseshoe kidneys
Trisomies 13 & 18

Trisomy 13



Scalp defects (eg
cutis aplasia)
Apneic spells
Midline brain defects

Trisomy 18



Congenital heart
defects
Flexion deformities
of extremities
Hypertonia
Both Trisomies 13 & 18

Congenital heart defects


Trisomy 18: VSD, ASD, PDA, PS
Trisomy 13: VSD, ASD, PDA, dextrocardia
Cryptorchidism
 Low set abnormal ears
 Microopthalmia
 Severe mental retardation

Down Syndrome



Trisomy 21
1/600
Causes

Full 21 trisomy 94%



Nondysjunction
Mosaic 2%
Translocation 3%
Facial Features of Down
Syndrome

Facies:






Upslanting palpebral
fissures
Epicanthal folds
Brushfield spots
Flat nasal bridge
Small mouth and
relative macroglossia
Short neck,
redundant skin folds
Note: epicanthal fold and
brushfield spot
Other Features of Down
Syndrome (MSK etc)

MSK







Simian crease
5th finger clinodactyly
Brachydactyly
Short stature
Sandal toes
Atlanto-axial
instability
Flattened occiput

Cardiac


Cognitive deficits


IQ usu 20 – 80
GI





AVSD, VSD, ASD, PDA
Duodenal atresia
Hirshprungs
Celiac disease
Constipation
Hypothyroidism >
hyperthyroidism
Other Features of Down
Syndrome

Respiratory / ENT



Heme


OSA
Serous OM



Complications


Leukemoid reaction
Neurologic


Hearing loss: CHL, SNHL,
mixed
Myopia
Hypotonia
Autism


Leukemia
Early Alzheimers
(100%, < 40y)
Atlantoaxial
instability
Depression
Health Surveillance Down
Syndrome

Birth





Echo
AUS
Hearing screen
Thyroid screen
CBC

Thyroid


Birth, 6 mo, 1y and
annually
Vision


Visual acuity
annually
Ophtho q 2y (50%
refractive errors
between 3 – 5y),
q 1y after 5y
Health Surveillance Down
Syndrome

Audiograms


Annually
Lateral neck Xrays for AAI

If participating in Special Olympics or
symptomatic
Monitor for OSA
 Celiac Screen

Just a few quick things…

For the MOST part, genetic syndromes are
autosomal dominant (AD)

Except:



VATER (Association)
Bardet-Biedel (AR)
Metabolic disorders are autosomal recessive
(AR)

Except:


Ornithine transcarbamylase (Urea cycle defect) XL
Hunter syndrome (Mucopolysaccharidase II) XL
Just a few quick things…

And for the most part,
immunodeficiencies are XL

Except
Leukocyte Adhesion Defect (AR)
 Hyper IgE Syndrome

Thank you!
Name 2 syndromes associated
with Long QT
Romano Ward
Syndrome

AD
Jervell and LangeNielsen Syndrome


AR
Associated with
deafness
Name 2 syndromes associated
with Craniosynostosis
Crouzon Syndrome




AD
Brachycephaly
(coronal suture)
Ocular proptosis
Hypoplasia of maxilla

Apert Syndrome



Sporadic
Multiple sutures
involved
Syndactyly of 2, 3, 4
A Couple Other Syndromes to
Know
…. If you happen to be studying for
your exam
Name one syndrome with:
Meckel-Gruber Syndrome



AR
Live a few days to
weeks
Die from renal or CNS
defects



Occipital
encephalomyelocele
Microcephaly with sloping
forehead
Cerebral or cerebellar
hypopplasia




Cleft palate
Talipes
Renal dysplasia
Cryptorchidism
Miller-Dieker Syndrome


Microdeletion
Facies





Microcephaly with
bitemporal narrowing
Furrowing of central
forehead
Low set ears
Small nose
Broad nasal bridge

CNS



Lissencephaly
Heterotopias
Mental deficiency
Three things associated with:
Prune Belly Syndrome

Eagle-Barrett
Syndrome



Absence of
abdominal
musculature
Cryptorchidism
Renal anomalies




Dysplastic kidneys
PUV
VUR
Hydronephrosis