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239 Cards in this Set

  • Front
  • Back
Goldenhar Syndrome
Extreme end of oculoauriculovertebral (OAV) spectrum (maldevelopment of 1st and 2nd branchial arches)

Mostly sporadic

Unilateral microtia
Hemifacial microsomia
Mandibular hypoplasia
Microstomia (cleft at side of mouth)
Epibulbar dermoids
Vertebral anomalies (malformed, fused, hemivertebrae)
Cardiac anomalies
Hemifacial Microsomia (HFM)
Mild end of oculoauriculovertebral (OAV) spectrum (maldevelopment of 1st and 2nd branchial arches)

Multifactorial, cause unknown

Unilateral microtia
Mandibular hypoplasia
Microstomia (cleft at side of mouth)
Townes-Brocks syndrome (TBS)
mutations in SALL1
Autosomal dominant

Imperforate Anus
Dysplastic Ears (preauricular tags, sensorineural and/or conductive hearing loss)
Thumb malformations (triphalangial, or duplication of thumb)

Renal (horseshoe kidney, hypoplasia, polycystic kidneys, reflux)
Intellectual disability in 10%
General Traits of Craniofacial Microsomia (CFM)
Malformation of 1st and 2nd branchial arches

Mostly simplex with unknown etiology
Recurrence risks are empiric
(2-3% sibs if no family history)

Facial asymmetry
Maxillary and/or mandibular hypoplasia
Preauricular or facial tags
Ear malformations (microtia, anotia, aural atresia)
Hearing loss (conductive, sensory, or mixed)
Cranial nerve anomalies (facial palsy, sensorineural hearing loss, impaired extraocular movements)
Respiratory compromise from severe mandibular hypoplasia,
Cleft lip and/or palate (macrostomia most common, lateral)
Vertebral (malformed, fused, hemivertebrae)
Epibulbar dermoids (benign tumor in the cornea)
Cardiac (TOF, VSD, transposition great vessels, aortic arch anomalies)
Renal (absent kidney, double ureter, hydronephrosis, etc.)
Limb anomalies (radial or ulnar ray)
Microcephaly, hydrocephaly, brain malformations (hypoplasia of corpus callosum, Arnold-Chiari malformation, holoprosencephaly)
When do neural crest cells migrate to the branchial arches?
4th week of gestation

Each arch 3 layers:
1) Endoderm
2) Ectomesenchyme with mesoderm
3) Ectoderm

Form: muscle, artery, nerve, cartilage
Treacher Collins Syndrome (TCS)
Mutations in TCOF1
60% de novo
Autosomal dominant
40-50% have conductive hearing loss (bones of middle ear)

Malar (zygomatic) hypoplasia = no cheekbones
Mandibular hypoplasia
Microtia (external ear abnormalities)
Leads to conductive hearing loss
Downslanting palpebral fissures
Coloboma of lower eyelid
Deficient lower eyelashes
Scalp hair in sideburn area
Normal intelligence

Cleft palate
Choanal stenosis or atresia
Nager Syndrome
Facial anomalies and PREaxial limb anomalies
Rare, mostly simplex, cause unknown
Autosomal dominant
(AD, AR reported)

Hypoplasia/absence of thumbs
Triphalangeal thumbs
Hypoplasia/absence of radius
Radioulnar synostosis
Short forearms
Malar hypoplasia
Downslanting palpebral fissures
Lower eyelid coloboma
Absence of lower eyelashes
Lowset, posteriorly rotated ears
Preauricular tags, atresia of external ear canal
Cleft lip +/- palate
Severe micrognathia
Miller Syndrome
Facial anomalies and POSTaxial limb anomalies
Autosomal Recessive, Rare

Hypoplasia/syndactyly/absence of pinky and 3rd or 4th digits in some cases
Hypoplasia of ulna (shortening of forearms)
Malar hypoplasia
Severe Micrognathia
Cleft lip +/- palate
Small cup-shaped ears, lowset
Conductive hearing loss
Lower eyelid coloboma or drooping
Supernumerary nipples
CHARGE syndrome
CHD7 mutations in 60-65%
Autosomal Dominant
Hearing loss: cochlear or VIII nerve

Coloboma (iris, retina, optic nerve)
Heart defects
Atresia of choanae
Retarded growth and development
Genital abnormalities
Ear anomalies (no lobule)/hearing loss

Mondini defect of the chochlea (fewer turns)
Absent or hypoplastic semicircular canals
Affects balance
DO CT OF TEMPORAL BONE for diagnosis

Undescended testicles
Cranial nerve dysfunction
(facial nerve palsy, hearing, swallowing)
Branchiootorenal (BOR) syndrome
Autosomal dominant
EYA1 (BOR1 locus) 40%
SIX5 (BOR2) 5%
SIX1 <1%

Branchial cleft anomalies (fistulae)
Malformation of the outer, middle, inner ear structures
Conductive, sensorineural or mixed hearing loss
Renal malformations
Lacrimal duct stenosis (no TEARS)

Preauricular ear pits, lop ear (overfolded helix), microtia, anotia
Environmental causes of craniofacial microsomia
Diabetic mother
Multiple gestation
Vasoactive drugs (Advil/ibuprofen, aspirin, pseudoephedrine)
Accutane during first trimester (abnormal neural crest migration)

Associated with:
Maternal use of ART
Second trimester bleeding
VACTERL association
Vertebral anomalies
Anal atresia
Cardiac anomalies
TracheoEsophageal atresia
Renal anomalies
Limb anomalies

Proximally place thumb
Radial aplasia
Humeral hypoplasia

No molecular test
Do SALL1 sequencing to rule out Townes-Brocks syndrome
Most common form of oral clefting associated with Craniofacial Microsomia
Unilateral macrostomia
(lateral cleft at side of the mouth)

All types of cleft lip and/or palate can be observed
What genetic changes can cause Craniofacial Microsomia?
Most cases simplex (single occurrance in the family)

Multifactorial inheritance (3-5% recurrence risk)
Single-gene mutations (1-2% of families show Autosomal Dominant; AR rare)

Familial more likely to be bilateral; Simplex shows more hearing loss and aural atresia

Chromosomal causes (deletion 5p, chroms 18, 22 anomalies)
What testing to do in Craniofacial Microsomia?
Hearing testing (even if passed newborn screening)
X-rays of spine (AP and lateral, especially cervical spine)
Renal ultrasound
Consider Echocardiogram
CT scan of temporal bone at 5 years old
Karyotype and aCGH if multiple anomalies or developmental delays
When does lip close during gestation?
When does palate close?
Lip closes: 6-7 weeks of gestation
Palate closes 7-8 weeks (by 12)

Failure of lip fusion may interfere with closure of palatal shelves
Incidence of cleft lip +/- palate
Incidence of cleft palate alone

Which differs with ethnicity, sex?
Cleft lip +/- palate: 1/750
(50% of cleft lip have cleft palate)
Differs with ethnicity
Native American>Asian>Caucasian>African American

Cleft palate: 1/2500
Same for males and females
More likely to be syndromic
Includes bifid uvula
Also submucous cleft palate (VPI)-imperfect union of muscles
Environmental risk factors for cleft lip +/- cleft palate
Antiepileptic drugs (phenytoin)
Diabetic mother (gestational diabetes)
How much of cleft lip +/- palate is isolated versus syndromic?

How about cleft palate?
Cleft lip +/- palate: 70% isolated
Multifactorial inheritance

30% not isolated, possibly syndromic

Cleft palate: 50% isolated
50% syndromic
Increased risk of intellectual disabilities
Clinical issues associated with oral clefting
Feeding difficulties
Otitis media
Hearing loss
Speech difficulties
Syndromes with cleft lip +/- palate
Van der Woude syndrome
CHARGE syndrome
Waardenburg syndrome (type 1 and 2A)-examine eyes
Ectrodactyly ectodermal dysplasia and clefting syndrome
Ankyloblepharon ectodermal dysplasia and clefting syndrome
Early amnion rupture sequence
OpitzG/BBB syndrome
Basal Cell Nevus syndrome
Syndromes associated with cleft palate alone
22q11.2 deletion syndrome (Velocardiofacial syndrome)
Stickler syndrome
Pierre-Robin sequence
Smith-Lemli-Opitz syndrome
Kabuki syndrome
Pallister-Hall syndrome
Treacher-Collins syndrome
Nager syndrome
Miller syndrome (rarely cleft lip)
Waardenburg syndrome (type 1 and 2A-examine eyes
Fanconi anemia
Ataxia Telangiectasia
Smith-Lemli-Opitz syndrome
Kabuki syndrome
Pallister-Hall syndrome
Meier-Gorlin syndrome (small, well-formed ears; absent patellae)
Prader-Willi/Angelman (15q11.2)
Smith-Magenis (17p11.2)
Miller-Dieker (17p13.3)
Cri du Chat or 5p- syndrome 5p15)
Wolf-Hirschorn or 4p- syndrome (4p16)
Williams syndrome (7q11.23)
Langer-Giedion (8q24)
1p36 deletion syndrome (not strong phenotype)
Recurrence risks for cleft lip +/- palate

Recurrence risks for cleft palate alone
Up to 50% if is syndromic; rare autosomal dominant families
Otherwise, multifactorial: 3-5%

Sibs of cleft lip +/- palate: 4% (2% if no one else affected)
If another sib or a parent affected: 10-20%
Children of cleft lip +/- palate: 4%

Cleft palate:
Sibs 1.8%
If two sibs affected: 8%
Children 3%
Prenatal detection/prevention of cleft lip +/- palate?
Can sometimes detect cleft lip in second trimester Level 2 ultrasound (not usually cleft palate)

Folic acid may reduce clefting
Microtia incidence
How varies by ethnicity, sex
More common in Navajo Indians

Right ear more affected than left
Environmental risk factors for microtia
Diabetic mother
Born at altitude
Alcohol use
What percentage microtia sporadic (first case in family, empiric recurrence risk)
2/3 or more (2% recurrence risk in sibs and offspring)

May be familial (mostly autosomal dominant)
or syndromic
Anomalies associated with microtia
Hearing deficits (may be contralateral)
Facial clefts
Cardiac anomalies
Vertebral anomalies
Limb anomalies
Renal anomalies
When a patient has microtia, what do you look for on physical exam?
Facial asymmetry
Epibulbar dermoids (tumors of sclera)
Facial nerve weakness
Macrostomia (lateral cleft of mouth)
When are these repairs done?

Cleft lip
Cleft palate
Cleft lip:
Cleft palate:

Microtia: 4-6 years
When pinna is 80% of adult size
Syndromes associated with microtia
Hemifacial Microsomia/Goldenhar
Nager syndrome
Miller syndrome
Treacher-Collins syndrome
If see cleft palate in setting of Pierre-Robin sequence, what 2 syndromes think of?
22q11.2 deletion syndrome
Stickler syndrome
Pierre-Robin Sequence
Cleft palate (U-shaped)

Advance jaw if difficulties in airway, feeding

Isolated or part of a syndrome
22q11.2, Stickler
22q11.2 deletion syndrome
1/6000 Caucasian, Af-Am, Asians
1/3800 Hispanics
93% new deletion, 7% inherited
Autosomal Dominant

Impaired T-cell immunity (77%)
Conotruncal cardiac malformations (74%)
Learning problems (70-90%)
Palatal abnormalities (69%)
Hypocalcemia (50%)
Renal anomalies (37%)
Feeding problems (30%)

Lateral buildup on nasal bridge
Columnar nose
Bulbous nasal tip
Small palpebral fissures
Micrognathia/Robin sequence
Slender fingers and toes
Minor ear anomalies
Percentage of children with congenital heart disease who have 22q11.2
1/68 of all congential heart disease

50-80% of interrupted aortic arch
30-40% of truncus arteriosus
16% of Tetralogy of Fallot

5-8% of children with cleft palate
Heart defects most common in 22q11.2
Tetralogy of Fallot (22%)
Interrupted aortic arch (15%)
Ventricular septal defect (13%)
Truncus arteriosus (7%)
Atrial septal defect (3%)
Van der Woude syndrome
Autosomal dominant
Mutations in IRF-6

Cleft lip
Cleft palate
Lower lip pits or mounds
Stickler Syndrome
Autosomal dominant connective tissue disorder
COL2A1, COL11A1, COL11A2
Majority of cases inherited

Incidence 1/10,000

Myopia (nearsightedness), Cataract
Retinal detachment
Hearing loss (conductive and sensorineural)
Underdevelopment of the midface
Cleft palate, Robin sequence
Premature arthritis
Vitreous of the eye: findings
Joint hypermobility
Recurrence risk: Unilateral, isolated ear anomalies
Low (although possible autosomal dominant families)

Multifactorial: 3-5%
Midline cleft lip-what need to consider?

Orofacialdigital syndrome
Short rib polydactyly
Chiari Malformation
Type I usually asymptomatic
Type II Arnold-Chiari malformation more severe (usually w/myelomeningocele)
Type III worst

Bony space at rear of the skull is smaller than normal,
Cerebellum and brainstem pushed downward
Blocks flow of cerebrospinal fluid (hydrocephalus)
Dizziness, muscle weakness, numbness, vision problems, headache, and problems with balance and coordination
Least common form of inheritance for genetic conditions?
Y linked
or mitochondrial
What do you never see in X-linked disease?

What will recessive look like when passed from a father?
Male to male transmission

Recessive: Affected father passes it on
All girls are carriers, no boys affected

All girls affected
no boys affected
Ataxia Telangectasia
ATM gene
Finds DS breaks in DNA, arrests at checkpoint
Amish founder mutation

See 7;14 translocation in peripheral blood
Elevated serum AFP

Progressive cerebellar ataxia
Oculomotor apraxia
Conjunctival telangiectasia
Sensitivity to ionizing radiation
Lymphoma, leukemia risk

Wheelchair by age 10
Carriers at risk for disease in what conditions?
Fabry (women at risk for cardiomyopathy, kidney, neuropathy)
DMD (women at risk for dilated cardiomyopathy)

Fragile X premutation (FRAXTAS, POF)
Ataxia Telangectasia (breast cancer)
Fragile X syndrome
FMR1 gene
CGG repeats
3' untranslated region
Gene methylation, loss of function
Expansion through the mother
>200 repeats = disease

Moderate MR in males; mild in females (50%)
Large head, long face, prominent forehead, jaw
Protruding ears
Joint laxity
Large testes after puberty
Autism spectrum disorder common (25%)
Hyperactivity, hand flapping, hand biting, temper tantrums
Delayed milestones (especially speech)
Myotonic Dystrophy
Triplet repeat disease
Expansion through the mother

5-34 normal
35-49 premutation
What is the minimum recurrence risk for a disease?
New mutation rate

Floppy, hypotonia
Feeding difficulties
Hypogonadism, undescended testicles
Are there autosomal dominant mitochondrial conditions?
No. All recessive.

Complex 2 has no MT-encoded proteins in it. Only one totally nuclear encoded.
With 3 or more miscarriages, what is the chance of carrying a translocation?
What do we think of if a baby was delivered by C-section?
If in the breech position, could be because wasn't moving as much as normal
Types of microcephaly

Acquired (suggests a metabolic condition)
Developmental milestones:
Head control
Roll over
Single words
String together 2 words
Head control: 2 months
Roll over: 3-4 months
Sit: 6 months
Crawl: 9 months
Walk: 1 year (to 15 months)
Single words: 1 year
String together 2 words: 2 years
What IQ qualifies as mentally retarded?
100 is average IQ
MR is <85
Down syndrome
Upslanting palpebral fissures
Epicanthal folds
Speckles in iris
Flat nasal bridge
Low set, retroverted ears
Overfolded helices
Single palmar crease (sign of less movement)

Low muscle tone (tongue lolls)

Risk of early Alzheimers
Leukemia TKTKTK
Trisomy 18
No creases at outer joint of fingertips
(a sign of less in utero movement)
Reasons for delayed motor milestones
Big heavy head (achondroplasia)
Fat baby
Frequency of nonpaternity?

Arskog syndrome

Shawl scrotum
Distal swan-neck shape to fingers (can't straighten them)
Cystic Fibrosis genetics
CFTR gene

When see R117H, reflex test:
5T/7T/9T variant in noncoding region
R117H plus 5T = full mutation

5T alone (with mutation on other chromosome)
Bilateral absence of the vas deferens, mildest phenotype

23 mutations on panel present in at least 0.1% patients
Carrier advantages
Sickle cell: Malaria-infected cells sickle and are cleared from body

Cystic Fibrosis: CFTR channels won't pick up typhoid fever from intestines
Variegate porphyria
Defect in breaking down red blood cells
Ellis van Crevald TKTKTK
Skeletal dysplasia prevalent in the Pennsylvania Amish
Metachromatic leukodystrophy
Degeneration of white matter in brain

1/9 carrier frequency in Inuits
Type of dwarfism that is recessive
Diastrophic dysplasia
Risk of birth defects:

-General pop
-First cousin mating
-Sib mating (or other first-degree)
Risk of birth defects:

-General pop: 3-4%
-First cousin mating: 6% (double)
-Sib mating >50% (share half genes)
HFE gene
Autosomal recessive
Absorb and store too much iron
Builds up in pancreas, heart, liver

Cirrhosis and liver failure

1/9 are carriers of C282Y TKTKTK
Less serious in women (menstruate)
Global distribution of alpha and beta thalassemias
Alpha: Asia
Alpha + Beta: India
Beta: Mediterranean
How high a carrier frequency is considered high enough to screen for?
1/100 as rule of thumb
What is the benefit of Genzyme's expanded CF panel?
Additional mutations common in Hispanic and African Americans

If see echogenic bowel and family is Hispanic

If already know wife a carrier, SEQUENCING gives best chance of picking up something in the husband
Do sickle cell carriers have anemia and a low MCV?
No. So have to do hemoglobin electrophoresis to screen

African-American carrier frequency =
1/12 TKTK
Tay Sachs screening for a pregnant woman
Mutation analysis
Do enzyme analysis in her partner if not Ashkenazi Jewish (mutation testing has good pickup only for AJ)
Which type of hemoglobin rises in Beta-thalassemia trait (carriers)?
Hbg A2 (alpha2-delta2; usually up to age 6 months) always
Hbg F (alpha2-gamma2; usually fetal hemoglobin) sometimes
Fanconi anemia
One of the AJ disorders

Bone marrow failure
Drop in RBC, WBC, platelets

Duchenne Muscular Dystrophy
High rate of new mutations

If no family history, 2/3 mothers are carriers
1/3 de novo

65% deletions
10% duplications
30% small mutations detected by sequencing
Common X-linked metabolic disorders
OTC deficiency (urea cycle)
Hunter syndrome (lysosomal storage disorder, MPS type II)
How does a complete mole occur?
Trisomic rescue

Two sperm fertilize an egg
Kick out the female DNA
Angelman syndrome characteristics
"Happy puppet"
No speech at all
Severe MR
Jerky gait
Large jaw, protruding tongue
Inappropriate laughter
Postured like a marionette

Paternal UPD is on rare mechanism
Angelman syndrome mechanisms
Deletion 68%
UBE3A mutation 11%
UPD (paternal) 7%
Lower than in Prader-Willi
Imprinting defect 0.5%
Hearing Loss
Modes of inheritance?
Autosomal dominant
Autosomal recessive
Stats on childhood hearing loss
1/1000 born deaf
1/300 significant hearing impairment

60% is genetic
40% environmental

OF genetic:
70% non-syndromic
30% syndromic

OF non-syndromic
80% autosomal recessive
20% autosomal dominant
Most commonly affected gene for non-syndromic hearing loss?
GJB2 (Connexin 26)
Connexin deafness
10% of all congenital hearing loss
70% of all non-syndromic, recessive hearing loss

Carrier frequency
2-3% Caucasians (similar to CF)
4-5% Ashkenazi Jews
1% Japanese
Types of mutations in connexins
Homozygous (AR) point mutations

Frameshift mutations
35delG mutation in Caucasians

Means gap junctions can't function

(a few dominant mutations like R75W)
(V27I is just a polymorphism)
GJB2 (connexin 26) gene structure
A single coding exon

Sequencing primers cover entire sequence
Familial Hypercholesterolemia (FH)
Autosomal dominant
LDLR mutations (Seq; Del/Dup)
High LDL "Bad" Cholesterol
Receptor can't remove LDL from blood
Begins at birth
Risk of early heart attack and stroke
Homozygotes more severe

Locus on Chromosome 19

Fatty skin deposits called xanthomas (elbows, knees, buttocks, tendons, and around the cornea of the eye)

Cholesterol deposits in eyelids (xanthelasmas)

Chest pain (angina); other signs CAD
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
Occurs in males (some females): 45%/16%
With Fragile X (FMR1) Premutation
55-200 repeats

Progressive cerebellar ataxia
Intention tremor
Cerebellar white matter lesions on MRI
FMR1-Related Primary Ovarian Failure (POF)
Occurs in ~20% females
with a Fragile X (FMR1) Premutation
Age < 40
55-200 repeats
Fragile X Repeat Lengths
CGG Repeats
Expansion in the mother
Father transmits his allele to ALL daughters (NO sons)

5-44 Normal
45-54 Borderline
55-200 Premutation
> 200 Full mutation

Interrupting AGG repeats make more stable
Conditions caused by chromosome deletions
Imprinted domain on 11p15.5
Parent of origin effects
Growth factors and tumor suppressor genes

Maternal methylation errors
"Differentially methylated regions"
50% loss of methylation at DMR2
(antisense RNA now inactivates cell cycle regulator gene CDKN1C )

20% Paternal UPD
(Now 2x IGF2 paternally expressed AND DMR2 shut down)
usually segmental, mitotic error
DMR1 has H19 (noncoding mRNA) and IGF2

10% CDKN1C mutations (gene is normally maternally expressed)

(other forms low recurrence risk)
Overgrowth syndrome (1/13,700)
Prematurity, polyhydramnios, large placenta
Umbilical hernia/omphalocele
Embryonal tumors (7.5%)

Renal abnormalities
Earlobe creases and helical pits
See tops of whites of eyes
Newborn hypoglycemia
(pancreatic beta-cell hypertrophy)
Clitoral/genitalia enlargement
Cardiac malformations, cardiomyopathy
Growth slows 7-8 years of age
Sotos syndrome
Autosomal dominant
NSD1, histone-lysine N-methyltransferase
Overgrowth in all parameters
(vs BW internal organs out of proportion)

5q35 microdeletion including NSD1 (15%...70% Japanese)
NSD1 sequencing (most non-Japanese)

Sparse frontotemporal hair
High bossed forehead
Long narrow face, small jaw, pointed chin
Mild to severe learning disability
Delayed motor skills
Tall stature and increased body mass
Low tumor risk
Diabetic mother
Big baby
Beckwith-Wiedeman and monozygotic twinning
Increased chance of twins in BWS
Majority female
(one has, one not)

Maternal loss of methylation at DMR2
Risks of Beckwith-Wiedeman
20% infant mortality
Macroglossia and airway insufficiency
Hypoglycemia can harm CNS
Beckwith-Wiedemann Inheritance
85% no family history
10-15% familial
AD with maternal transmission
Molecular testing for Beckwith-Wiedemann
If familial:
1) High resolution karyotype
2) CDKN1C mutation scanning

If sporadic:
1) High resolution karyotype (do first if MR)
2) Methylation studies (serves as UPD study too since both DMR1 and DMR2 will be abnormal if there is UPD)
Tumor risks for Beckwith-Wiedemann
(abdominal US every 3 months until age 8)
Wilms tumor 43%

No risk with familial CDKN1C mutations
Loss of methylation at DMR2 other tumor types

Hemihyperplasia, nephromegaly means greater risk

Highest with increased IGF2:
11p15 paternal UPD
H19 hypermethylation

Hepatoblastoma 20%
Adrenocortical cardinoma 7%
Rhabdomyosarcoma 6%
Conditions involving imprinted genes
Isolated Wilms tumor (IGH2/H19 locus)

Transient neonatal diabetes
Carotid body tumors
Truisms about imprinted genes
CpG methylation
Tend to occur in clusters
Antisense transcripts expressed on the other allele
Long-range cis-acting mechanisms
What is the risk with IVF/ART?
Loss of maternal imprinting

-DMR2 in Beckwith-Wiedemann
-Angelman syndrome also loss of maternal imprinting center
Differential for Beckwith-Wiedemann
Sotos syndrome
Simpson Golabi Behmel
Perlman syndrome
Costello syndrome
Simpson Golabi Behmel
X-linked recessive
Mutations in GPC3

High rate cardiac defects
Supernumerary nipples
Perlman Syndrome
Autosomal recessive (unknown gene)

Risk of bilateral Wilms tumor
Characteristic face
Costello syndrome
Autosomal dominant
HRAS mutations

Bladder cancer

Overgrowth due to edema
Strabismus, nystagmus, myopia, astigmatism
Bitemporal narrowing
Cardiac defects
Failure to thrive "like trying to die"
Motor and speech delay
Later distinctive facies
Skin looks like has a tan
Doughy velvety skin with deep wrinkles
Warty growths around anus, nose
Retention hyperkeratosis
Fine, sparse, curly hair
Russell Silver Syndrome
Undergrowth (1/75,000)
Assymmetry due to mosaicism
Normal intelligence
Short stature
Normal head circumference and growth velocity
Head LOOKS macrocephalic
5th finger clinodactyly
Small triangular face, thin upper lip
Mechanism of Russell Silver Syndrome
OPPOSITE of Beckwith-Wiedemann
Imprinting defect at DMR1
(H19, IGR2)

50% Paternal hypomethylation at DMR1
Decreased IGF2 expression
(Missing paternal contribution)

10% Maternal UPD chromosome 7 (!!)

If duplication of 11p, can alternate BWS and RSS depending on parent of origin.
(Paternal duplication=BWS)
Normal hemoglobin in RBC
Fetal: Hgb F (alpha2-gamma2)

Hgb F (alpha2-gamma2) 60% lasts to 3 months
Hgb A (alpha2-beta2) 40%
Hgb A2 (alpha2-delta2) 1%

Adult: Hgb A (alpha2-beta2) 98%
Hgb A2 (alpha2-delta2) 1-3%
What is thalassemia?
Diminished synthesis of one or more globin chains that combine to form hemoglobin

2 beta genes (Chrom 11)
4 alpha genes (Chrom 16)
Most prevalent in:
Southeast Asian (into India) --/aa CIS
American Blacks -a/-a TRANS

Less common in Mediterranean
Alpha-thalassemia subtypes
1 gene deleted (or Hbg constant spring)
alpha-thal trait (silent carrier: -a/aa)
Blacks get, Asians not generally

2 genes deleted
alpha-thal trait
microcytosis, mild anemia

3 genes deleted
Hemoglobin H disease
Chronic hemolytic anemia
Asians get, not blacks

4 genes deleted
Barts Hgb
Fetal hydrops (--/--)
Asians get, not blacks
Why is it called Hgb H disease?
3 alpha chains missing
Lots of extra beta

4 betas aggregate to form "Hgb H"
Inclusions in the RBCs
Why is it called Bart's Hgb?
4 alpha chains missing
Lots of extra gamma in fetal life

4 gammas aggregate to form "Hgb Bart's"

Newborn screening looks for excess of this to diagnose Hgb H disease.
Why splenomegaly with alpha-thalassemia?
What other symptoms?
Spleen is site of fetal RBC production. Ramps up now to sustain the patient.

Pale, jaundiced
At risk for aplastic bone marrow crisis
Extra billirubin forms gallstones (pain)
What do if baby tests positive on newborn screening for Hgb H disease?
Genotype the parents
What do you do if see a low MCV?
Iron studies on patient
Test partner's MCV

If is alpha-thalassemia,
diagnosis of exclusion
Normal transferrin
Normal hemoglobin electrophoresis
(deletions, not mutations)
Why is the anemia hemolytic?
Hgb H (4 betas) aggregates
in old blood cells
causes cell membrane injury and hemolysis
Why do fetuses with alpha-hydrops die in utero?
Hgb H and Hgb Bart's can't carry oxygen as well
Die of hypoxia
Heart overworked
Cardiac failure

Carrying a hydrops baby can
Beta-thalassemia trait
Heterozygous for a beta mutation
Mild microcytic anemia
Hypochromia, basophilic stippling
Normal iron studies
Increased Hgb A2 (delta compensates)
Increased Hgb F (gamma compensates)
What are iron studies like in alpha- or beta-thalassemia?

Serum iron
Srum ferritin
TIBC (total iron binding capacity)
Homozygous beta-thalassemia
Increased Hgb A2 10% (delta compensates)
WAY Increased Hgb F 90% (gamma compensates)
What do excess alpha chains do in beta-thalassemia?
Don't aggregate
Free in bone marrow
Cause RBC membrane injury
Hemolysis before get out of bone marrow
Ineffective hematopoesis
Clinical features of beta-thalassemia
Not notice until 6 months of age, since
Hgb A2 (alpha2-delta2) until 6 months

Transfusion dependent (iron chelation)
Irritable, fatigue, anorexia
Heart murmur, cardiac dilation (overworked)
Yellow sclera and skin jaundice
Thalassemia facies
Abdominal distention
Why thalassemia facies and abdominal distension?
Extramedullary RBC production

Facies: frontal and parietal bossing
Enlargement of maxilla
Front teeth protrude, lip pushed up
Nose bridge broadened

Spleen and liver site of fetal RBC production
Big belly

Bone pain, risk of vertebral fractures or long bone fractures
What organs does iron overload affect?
Heart (arrhythmia, hypertrophy, death)
Pancreas (diabetes)
Liver (fibrosis, cirrhosis, death)
Decreased pituitary and sex hormones

Body doesn't excrete iron except through menstruation or blood letting
Velocardiofacial/DiGeorge deletion location
Prader-Willi/Angelman deletion location

Infancy: Severe hypotonia
Severe feeding difficulties

Later: Excessive eating
Morbid obesity
Cognitive impairment
Temper tantrums
Manipulative behavior, OCD

Absence of paternal PWS/AS region

Methylation testing
De novo, recc risk <1%

Self-injurious behavior
Mild to moderate MR
Sleep disturbance
Impulsivity, Inattention, Hyperactivity

Sterotyped behaviors:
finger lick and page flipping ("lick and flip")

Infant hypotonia, failure to thrive
Must be woken for feedings, lethargic
17p13.3 deletion
80% de novo
20% parent has a translocation

Deficient neuronal migration
"smooth brain"
Absent gyri (agyria) or abnormally wide gyri (pachygyria)

Characteristic facies
Severe neurologic abnormalities
Cri du Chat
5p- syndrome 5p15

Multiple congenital anomaly syndrome
Cat-like cry
Severe psychomotor and MR
4p- deletion syndrome (4p16)

'Greek warrior helmet appearance'
of the nose
Short philtrum
Epicanthal folds
Growth deficiency, hypotonia

Variable MR
Skeletal anomalies (60%-70%), Heart defects (~50%)
Conductive hearing loss (>40%), Urinary tract malformations (25%), Structural brain abnormalities (33%)
Williams syndrome
7q11.23 deletion syndrome
Includes ELN gene for elastin
Most de novo; AD

Connective tissue abnormalities Cardiovascular disease
(Elastin arteriopathy,
Supravalvular aortic stenosis, Hypertension)
Distinctive facies
Mild MR
Hoarse voice
Cocktail Party personality
Growth/endocrine abnormalities Early puberty
Hyperextensible joints
Delayed motor milestones
Sensorineural hearing loss
8q24 deletion syndrome
Includes EXT1

Multiple cartilage osteochondromas
Large, laterally protruding ears
Bulbous nose
Sparse scalp hair
Winged scapulae
Digital anomalies

Result from haploinsufficiency of TRPS1
1p36 deletion syndrome (not strong phenotype)
Most common terminal deletion syndrome
Facial features:
Straight eyebrows

Deep-set eyes, midface hypoplasia,
Broad and flat nasal root/bridge
Long philtrum, and pointed chin

Microcephaly, brachycephaly
Epicanthal folds
Large late-closing anterior fontanel
Posteriorly rotated, low-set, abnormally formed ears

MR, hypotonia, seizures
Structural brain abnormalities (88%)

Congenital heart defects (71%), Eye/vision problems (52%)
Hearing loss (47%)
Abnormalities external genitalia (25%)
Renal abnormalities (22%)
Angelman syndrome
Loss of maternally imprinted genes
Methylation analysis
UBE3A sequence analysis

Severe developmental delay, MR
No speech
Gait ataxia, tremulous limbs
Happy demeanor
Frequent laughing, smiling, excitability
Seizures are common
Ataxia Telangiectasia
ATM gene
Autosomal recessive

Sensitive to ionizing radiation

Progressive cerebellar ataxia Begins ages 1-4 years
Slurred speech
Oculomotor apraxia (bumpy visual tracking)
Telangiectasias of the conjunctivae
Frequent infections
Risk for malignancy
Leukemia, lymphoma

Premature aging, gray hair
Pallister-Hall syndrome
GLI3 gene
Autosomal dominant

Hypothalamic hamartoma,
Central and postaxial polydactyly,
Bifid epiglottis
Imperforate anus
Renal abnormalities

Neonates may die from untreated pituitary insufficiency (producing cortisol/adrenal insufficiency)
Meier-Gorlin syndrome
Autosomal recessive
Genes unknown

Small, well-formed ears
Absent patellae (kneecaps)
Short stature

Severe pre- and postnatal growth restriction
Bilateral microtia
Intellect usually normal
Smith-Lemli-Opitz syndrome
DHCR7 gene
Autosomal recessive

Abnormal cholesterol metabolism Deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase

Multiple anomaly syndrome:
Characteristic facial features
Microcephaly, MR
Postaxial polydactyly
2-3 syndactyly of the toes
Growth and mental retardation
Cleft palate
Hypospadias in males
Cardiac defects
Kabuki syndrome
MLL2 mutations
Autosomal dominant

1. Typical facial features
Elongated palpebral fissures
Eversion of lateral third of lower eyelid
Arched and broad eyebrows
Sparseness or notching at lateral third
Short columella with depressed nasal tip
Large, prominent, or cupped ears
Cleft lip and/or palate
Ear pits

2. Skeletal anomalies:
Butterfly vertebrae
Narrow intervertebral disc space Scoliosis
Brachydactyly V
Fifth finger clinodactyly

3. Persistence of fetal fingertip pads

4. Mild to moderate intellectual disability

5. Postnatal growth deficiency

Hearing loss
Autosomal recessive
At least 14 genes

Night-blindness by 7-8
Legally blind ~ 15.5 years

Cone-rod retinal dystrophy
Truncal obesity (weight gain in first year)
Postaxial polydactyly
Learning difficulties
Male hypogonadotrophic hypogonadism
Female genitourinary malformations
Renal dysfunction (mortality)
Conotruncal heart defects
Cardiac outflow tract defects

Tetralogy of Fallot
Pulmonary atresia
Double-outlet right ventricle Truncus arteriosus communis Aortic arch anomalies

1/4 to 1/3 of isolated nonsyndromic congenital heart defects

22q11.2 found in 30%
Timothy Syndrome (LQT 8)
Disorder of calcium channels
CACNA1C gene
Gain of function

Severe QT prolongation
Age of death: 2.5 years
Syndactyly of fingers (100%)
2-3 toe syndactyly
Cardiac defects (60%)
(patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy)
Dysmorphic faces
Developmental delays
Autistic symptoms (50%)
Andersen Tawil (LQT 7)
KCNJ2 mutations
Autosomal dominant
50% de novo

Periodic paralysis
(episodic flaccid muscle weakness)
Prolonged QT, ventricular arrhythmias

Dysmorphic features:
Low-set ears
Ocular hypertelorism
Small mandible
Fifth-digit clinodactyly
Short stature
Jervell and Lange-Nielsen syndrome
(also cause Romano-Ward)
Autosomal recessive

Third most common type of autosomal recessive syndromic hearing loss
Parents can have LQTS

Profound bilateral sensorineural hearing loss
QTc > 500 msec

Deaf child
Syncopal episodes during stress, exercise, or fright

Untreated, half die by age 15
Heritability of psych disorders
autism > schizophrenia > bipolar > major depression

90-100% for autism
70-90% for schizophrenia
XX for bipolar
30-40% for major depression
If parent has Type 2 diabetes (only one in family) what is risk to child?
If child has ASD but met language milestones they have
Asperger syndrome
Features of muscular dystrophy
A group of more than 30 inherited diseases

Muscle weakness
Loss of muscle tissue
Apparent lack of coordination
Joint fixations (contractures)
Usually symmetrical
Voluntary muscles are most affected
Prevalence of muscular dystrophies
Facioscapulohumeral muscular dystrophy
= 1/14,286

Duchenne and Becker Muscular dystrophy
= 1/20,000

Steinert myotonic dystrophy
= 1/22,222
Duchenne MD
Becker MD
X-linked inheritance
DMD is on Xp21.2

Caused by a defect in protein dystrophin
Involves the DMD gene
Mostly boys affected
Duchenne Muscular Dystrophy
Complete lack of dystrophin in muscles
(Female carriers at risk)

Most severe form
Onset in early childhood (< age 5)
Rapidly progressive
Wheelchair bound by age 12
Dilated cardiomyopathy by age 18
Death by 20s or early 30s (respiratory or cardiac failure)

Signs and symptoms
Delayed sitting, standing, walking
Waddling gait
Large calf muscles
Difficulty getting up from lying or sitting
Gower’s maneuver
Mild mental retardation, sometimes
Becker Muscular Dystrophy
Milder form
Abnormal quality or quantity of dystrophin
85% deletions (MORE THAN DMD)
10% duplications
10% small mutations

Symptoms similar to Duchenne
Onset later: around age 11
Sometimes not until mid-20s or even later
Progresses more slowly
Usually able to walk through teens, into 20s
Most frequent cause of death: heart failure
Result of dilated cardiomyopathy
Mean age of death in mid-40s
Spinal Muscular Atrophy
Autosomal recessive
Mutations in SMN (SMN2 compensates)

Poor muscle tone
Symmetric muscle weakness
Spares the face and ocular muscles
Fasciculations of the tongue
Absence of deep tendon reflexes
DMD gene
2.4 Mb of DNA
79 exons.
At least four promoters
Largest known human gene

Deletions, duplications
Smaller point mutations
Steinert Myotonic Dystrophy
Autosomal dominant
“CTG” repeat expansion in DMPK gene (19q13)

Multisystem disorder
Skeletal and smooth muscle
Onset in adulthood
Slow progression
Begins with distal muscles
Hands, feet, lower legs

Breathing affected along with
Heart Rhythm
Steinert Myotonic Dystrophy Signs
Myotonic Grip

Muscle weakness, pain, stiffness
Inability to relax muscles at will

Common causes of death
Respiratory failure
Heart arrhythmia
Mechanism of Myotonic Dystrophy?
CTG trinucleotide repeat
non-coding region of DMPK
Dystrophia myotonica protein kinase
Produces embryonic forms of protein through RNA splicing
"Toxic mRNA"

5-34 normal
45-49 premutation
>49 disease

The more CTG repeats, more severe
>1000-2000 repeats causes congenital form:

Maternal (sometimes paternal) expansion

Myopathic facies
Respiratory deficiency
Mental retardation
Facioscapularhumoral Muscular Distrophy (FSHD)
Most common form of muscular dystrophy

Last major type to have its genetic cause identified

Facial muscles
Scapular stabilizer muscles
Upper arm muscles
Can also affect:
Lower leg

Causes wasting of muscles in upper body
Scapular winging
Side-to-side asymmetry
Onset in teens or twenties
Slowly progressive
Disability often minor, 20% will need a wheelchair
Lifespan not affected
Unusual mechanism of FSHD
Autosomal dominant
Contraction of repeats!
Toxic gain of function from more DUX4 protein
1/3 de novo
Subtelomeric deletion on 4q

Deletion involves D4Z4 macrosatellite repeats
Located on 4q35
Each repeat 3.3kb long

Normal: 11 to 100 repeats
Pathogenic contraction: 1 to 10 repeats
Poly-A stable RNA
More full-length, embryonic-type Dux4 protein
Ehlers-Danlos Syndrome
Classic type
Classic type
(EDS type I and EDS type II)
Autosomal dominant
50% de novo
50% have mutations in Type V Collagen
COL5A1 or COL5A2

Connective tissue disorder
Skin hyperextensibility
Abnormal wound healing
Joint hypermobility

Hyperelastic, extensible skin
Velvety and smooth to touch
Fragile skin
Prone to splitting over knees, shins, etc
Wound healing delayed
Hypertrophic scars
Joint hypermobility
Easy bruising

Mitral and tricuspid valve prolapse
Aortic root dilatation
Spontaneous rupture of large arteries
EDS Hypermobility type (EDS type III)
Autosomal dominant
Gene unknown (TenascinX, TNXB, in some)
Joint hypermobility is the primary manifestation

Skin soft, velvety, may be mildly hyperextensible
Dislocations are common
Degenerative joint disease
Chronic pain
Easy bruising
Atrophic scarring makes you think more of CLASSIC EDS

Entirely a clinical diagnosis

An autosomal recessive form has TNXB (tenascin X) deficiency
EDS Vascular type (EDS type IV)
The one people fear
COL3A1 mutations

Thin, translucent skin
Easy bruising
Characteristic facial appearance
Aged-looking hands
Fragility of:
and/or uterus

Affected individuals are at risk for Arterial rupture and/or dissection
Gastrointestinal perforation or rupture
Uterine rupture during pregnancy

25% have a significant medical problem by age 20
80% by age 40 years
Median age of death is 48

The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical and/or molecular genetic testing. Biochemical studies in affected individuals demonstrate abnormal electrophoretic mobility and abnormal efficiency of secretion of type III procollagen by cultured dermal fibroblasts. Molecular genetic testing is used to identify mutations in COL3A1. Inheritance is autosomal dominant.
Loeys-Dietz Syndrome
Autosomal dominant
75% de novo

Vascular findings
Cerebral, thoracic, abdominal Arterial aneurysms and/or dissections
Skeletal manifestations:
Pectus excavatum or carinatum
Joint laxity
Talipes equinovarus (club foot)

Approximately 75% have LDS type I with craniofacial manifestations: Ocular hypertelorism
Bifid uvula/cleft palate
Craniosynostosis (saggital)

25% have LDS type II with cutaneous manifestations:
Velvety and translucent skin
Easy bruising
Atrophic scars

Aggressive arterial aneurysms
Mean age at death 26
Pregnancy-related complications: Death and uterine rupture
De novo in connective tissue disorders?
25% Marfan
50% EDS
75% Loeys-Dietz
Alport syndrome
Collagen IV-related
Component of basement membranes
Nephropathy leading to end-stage disease
Hearing loss, sensorineural
Postlingual >10 years old, progressive

Most commongly X-linked
85% X-linked COL4A5
15% Recessive COL4A3, COL4A4
rare-Dominant COL4A3
Ring chromosomes
Subtelomeric deletions in ring formation can cause MR
Nonsyndromic MT deafness
Caused by mutations in MT DNA
One gene (of the 2) makes sensitive to aminoglycoside antibiotics
Maternal inheritance
Start with targeted mutation analysis

Mutation in MT-RNR1
(encoding mitochondrial 12S ribosomal RNA)
Aminoglycoside ototoxicity and/or Late-onset sensorineural hearing loss.

or MT-TS1
(encoding MT tRNA serine 1)
Childhood onset of sensorineural hearing loss

Gentamycin, tobramycin, amikacin, kanamycin, or streptomycin
Incidence of Fragile X
1/4000 boys
1/6000 girls
Mechanism of Fragile X premutation
RNA toxicity
(is no hypermethylation with premutation)

Can also get learning difficulties
Executive function deficits
Prominent ears, flexible joints
Which RASopathy is not associated with increased cancer risk?
Osteogenesis Imperfecta
COL1A1 or COL1A2
7 types, 60-100% de novo
(the more severe, more likely de novo)
MOSTLY Autosomal dominant
1 Autosomal recessive (type VII)
1 Unknown

Brittle bone disease
Fractures with minimal or absent trauma
Blue sclera
Hearing loss after puberty
Dentinogenesis imperfecta (DI)
Short stature

Biochemical testing preferred
(i.e., analysis of structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts)

Can be done on CVS

OI Type II is prenatal lethal, hips in "frog leg" position
Prelingual hearing loss
Postlingual hearing loss
50-60% have a genetic origin
70% isolated, 30% syndromic
Recessive inheritance most common

Dominant inheritance most common
Environmental causes of hearing loss in children
Prenatal exposures:
CMV - first infection during pregnancy

Postnatal exposures:
H. flu (otitis media, meningitis)
Ototoxic drugs like gentamycin
with MT-RNR1 gene mutation
Phenocopy for congenital CMV infection
Autosomal recessive (rare dominant)

A subgroup of infants with AGS present at birth with abnormal neurologic findings
(calcification of basal ganglia, cerebral atrophy) hepatosplenomegaly
elevated liver enzymes

highly reminiscent of congenital infection
What can ventriculomegaly in the fetus indicate?
CMV infection
or abnormal brain development
What causes syndromic congental hearing loss most often?
Conductive or mixed
Problems with the way the ears are formed
Syndromic hearing loss
When to consider chromosome abnormality
Hearing loss
Global developmental delay/MR
Major malformations
Multiple minor anomalies
Growth retardation
Deletion 18q
Conductive hearing loss
Narrow or atretic ear canals
Global developmental delay/MR
Waardenburg syndrome
Most common AD syndromic hearing loss
Multiple genes (multiple types)
PAX3, paired box protein, HOX TF involved in melanocyte development

Sensorineural hearing loss in 70-85%
Pigmentary abnormalities of hair, iris, skin
White forelock/early graying
Monobrow, widow's peak
Heterochromia of the irides
Tubular nose, deficient nostrils
Inner canthi laterally displaced

Type IV has Hirschsprung disease
(and has an AR form)

Neural crest migration problems
May have neural tube defect
Most common forms of AD syndromic hearing loss?
1) Waardenburg syndrome
2) Branchio-oto-renal syndrome
Branchio-oto-renal syndrome
Second most common form of AD syndromic hearing loss
Usher syndrome
Autosomal recessive
Multiple genes (~11)
Majority due to MYO7A, USH2A: myosin VIIa, usherin

Most common AR syndromic hearing loss

Congenital profound sensorineural hearing loss
Retinitis pigmentosa (constricts visual field)
Fundoscopic findings AFTER first decade
Abnormal ERG between 2-4 years

Type I: Vestibular dysfunction, balance problems
Type II: Normal vestibular
Type III: Variable vestibular

Ask about sitting, walking, motor skill aquisition
Balance test
What are the most common AR syndromic forms of hearing loss?
1) Usher syndrome
2) Pendred syndrome
3) Jervell and Lange-Nielsen syndrome
Pendred syndrome
Autosomal recessive
SLC26A4 mutations
Chloride/Iodide exchanger in inner ear and thyroid
in 50% familial, 20% simplex cases

Second most common AR syndromic hearing loss

Severe to profound SNHL
Vestibular abnormalities:
Mondini dysplasia
Abnormal bony labyrinth
Enlarged vestibular aqueduct
Normal thyroid function, but
Goiter 75%

If Connexin testing fails, reflex to Pendred
When will a temporal CT scan help the diagnosis?
CHARGE syndrome
(Mondini dysplasia, absent vestibular)

Pendred syndrome
(Mondini dysplasia)
Peroxisomal disorders
Autosomal recessive

Severe progressive hearing loss
Retinitis pigmentosa
Seizure disorder
Elevanted very long chain fatty acids
Nonsyndromic hearing loss
Modes of inheritance
75-85% Autosomal recessive
15-25% Autosomal dominant
1-2% X-linked
<1% Mitochondrial
In recessive nonsyndromic hearing loss, what percentage have mutations involving DFNB1 locus?

DFNB1 is first-line testing
GJB2 (connexin 26)
GJB6 (connexin 30)

Gap junction proteins
Connexin 26
Autosomal recessive

In 40% of sporadic cases of deafness

Carrier frequency:
4% Ashkenazi Jews (167delT)
2-3% Caucasians (35delG)
1% Japanese (235delC)

Are some dominant mutations
With ectodermal dysplasia symptoms
Palmoplantar keratoderma
Normal nails
Evaluating a child with nonsyndromic severe-profound SNHL
Family history
Evaluate vestibular function
If delayed, consider ERG (Usher)
Connexin 26/30 mutations

CMV testing in neonatal period
Optho exam for CMV scarring
Can't look for retinitis pigmentosa till age 10
CT scan of temporal bone if progressive
(CHARGE, Pendred)
EKG for Jervell Lange-Nielsen
Thanatophoric dysplasia
De novo FGFR3 mutations
Autosomal dominant

Short-limbed dwarfism
Type I: bowed femurs
Cloverleaf skull deformity

Short ribs, narrow thorax
Distinctive facial features Brachydactyly
Redundant skin folds on limbs
Death by respiratory insufficiency shortly after birth
Hemophilia A
Factor VIII deficiency
The more common one (80% of cases)
Inversion of exon 22 affects 50% of severe, 20% all
Small gene defects 75% all
No promoter mutations

1/5000 males

Big gene product (2332 amino acids)
Hemophilia B
Factor IX deficiency
Small gene defects
Only 2% deletions

1/20,000 males
Smaller gene product: 415 amino acids
von Willebrand disease
1% of the population

This is a carrier for factor VIII
Causes platelets to adhere to e/o and to damaged endothelium

1/100 F=Male since autosomal

A total lack of von Willebrand factor looks like Hemophilia A
Features of hemophilias
X-linked recessive
30% of cases are new mutations
Expressed in males
Carried by females
Severity CONSISTENT between family members

Less than 50% of factor level causes disease
Severe when <1% enzyme activity
Treatment of hemophilias
Replace missing clotting protein
Antifibrinolytic agents to make clots stable

More deletions in hemophilia A (factor VIII) so get antibodies formed to infused clotting factors in 20-30% patients
How are hemophilias and vWD different?
Hemophilia A and B: X-linked recessive
von Willebrand: Autosomal Dominant
Factor V Leiden Thrombophilia
Increased clotting
Makes Factor V resistant to Protein C degradation

Deep venous thrombosis
Can be heterozygote
Or homozygote (higher risks)

Heterozygosity risks 2-3x:
Pregnancy loss

Fetal growth retardation
Placental abruption
General rule about sporadic X-linked disorders
2/3 of time mom is a carrier
--mutation occurred in HER FATHER

1/3 of time new mutation
--mutation occurred in MOM
Conditions with thoracic aortic aneurysm and mitral valve prolapse
Most common cause of inherited intellectual disability?
Fragile X

1/4000 males
1/6000 females
Where is the Fragile X repeat location?
In the promotor region
CpG shuts down gene activity
Cystic fibrosis symptoms
Reproductive system

Cough, wheezing
Failure to thrive
Loose fatty stools
Abdominal main
Male infertility due to
Congenital absence of vas deferens

Only 15% are pancreatic sufficient
Have a milder course

1300 mutations identified
23 mutation panel detects 94% in AJ
88% other Caucasian
Spinal muscular atrophy (SMA)
Autosomal recessive
SMN1 gene deletion (95%), conversion, mutation
"Survival motor neuron gene"
Accurate phenotype prediction not possible

SMN2 mRNA missing exon7
10% SMN2 normally spliced
0 copies, Lethal
2 Copies, Type I
4 copies, Type II
4-8 copies, Type III

1/10,000 incidence
1/50 carrier frequency

Tongue fasciculation
Weakness, poor suck and swallow
Aspiration pneumonia
Death: Respiratory failure
Range of severity Type I-III
Type II most common, onset by age 2, sit not walk, die adolescence

3-4% of pop has 2 copies of SMN1 on one chromosome
Not ID as carriers

ACMG, NOT ACOG, recc offer to all
ACOG: Family history, or request it
Diastrophic dysplasia
SLC26A2 sulfate transporter

Cystic ears
Hitchhiker thumbs

Limb shortening
Normal-sized skull
Slight trunk shortening
Hitchhiker thumbs
Small chest
Protuberant abdomen
Contractures of large joints
Dislocation of the radius
Cleft palate (in approximately one-third of individuals)
Cystic ear swelling in the neonatal period (in approximately two-thirds of infants with classic findings)

Other usual findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead
Diseases in which male gametes are more often mutated than female gametes
Hemophilia A (Factor VIII)
Lesh-Nyhan syndrome
Lesch-Nyhan syndrome
NOT a deletion syndrome
HPRT enzyme
X-linked recessive

Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs)

Motor dysfunction
Resembles cerebral palsy
Cognitive and behavioral disturbances

Hypotonia and developmental delay
Most never walk
Pyramidal involvement
(e.g., spasticity, hyperreflexia, extensor plantar reflexes) become evident

Hyperuricemia with kidney stones
Renal failure
HTT gene
1/20,000 people

CAG repeats (exon 1)
Toxic HTT protein, apoptosis
Forms inclusion bodies in brains
Basal ganglia and limbic system

Dysarthria - difficulty talking, slurring speech
Dysphagia - difficulty swallowing
Anticipation through the father

Chorea, movement disorder, tics, grimaces
Cognitive deficits, loss executive function
Psychiatric/emotional disturbances
Depression, disinhibition
35-45 years at onset
What are the repeat diseases?
Huntington's CAG (in coding region, polyglutamine)
TOXIC PROTEIN, apoptosis

Fragile X CGG (5' untranslated region)
Myotonic Dystrophy CTG (3' downstream untranslated, gene silencing, toxic RNA)
Friedreich Ataxia GAA (intronic, terminates transcription)

Kennedy disease
Spinocerebellar Ataxia (except type 8)
Spinobulbar muscular atrophy
Huntington's repeat sizes
10-26 Normal
27-35 Pre-mutation
36-39 Reduced penetrance
40 Mutation
60 Juvenile onset

PCR can detect up to 100 repeats
Southern blot for larger
Frontotemporal dementia
10% of cases AD
5% have MAPT (tau) mutation
--missense, toxic gain of function
5% have GRN mutation
--haploinsufficiency of progranulin
ubiquitin inclusions

Most common dementia <60
Younger than Alzheimer's

Atrophy of frontal lobes

Progressive decline in
Executive function (judgment, planning)
Later apathy
Tuberous Sclerosis
TSC1 and TSC2 sequencing
(Hamartin and Tuberin)
Autosomal dominant
2/3 de novo

Shagreen patch
Subependymal glial nodules
Cortical tubers
Cardiac rhabdomyoma

TSC2/PCKD contiguous gene deletion with features of TS, PKD
Leopard syndrome
PTPN11 (SHP2 protein, loss of function)
OPPOSITE of Noonan mutations
Autosomal dominant

Electrocardiographic conduction anomalies
Ocular hypertelorism
Pulmonary stenosis
Abnormal genitalia
Retardation of growth
Deafness, sensorineural
Noonan syndrome
PTPN11 GAIN of function
Activating mutations Ras/MAPK pathway
(opposite of Leopard)
Autosomal dominant

Increased risk leukemia

"Male Turner Syndrome"
Learning disabilities (25%), delayed speech
Short stature
Pulmonary valve stenosis (50%)
Hypertrophic cardiomyopathy (30%)
Renal malformation
Bleeding disorders

Tall forehead
Down slanting palpebral fissures
Low-set posteriorly rotated ears
Deep philtrum
Short neck
Kyphoscoliotic type
Deficiency in enzyme crosslinks collagen

Marfanoid habitus
Rupture of medium-sized arteries
Aortic root dilation
Scleral fragility
Joint laxity
Hyperextensible, friable skin
Widened, atrophic scars
Easy bruising
FGFR-related craniosynostosis
FGFR1, 2, 3
Increased mutations with paternal age
Autosomal dominant inheritance

Bicoronal craniosynostosis
or Cloverleaf skull
Variable hand and foot anomalies
Developmental delay
Hearing loss
Visual impairment--cranial nerve compression
Otitis media
MR (greatest risk in Alpert)

Downslanting palpebral fissures
Midface hypoplasia
Choanal atresia
Small beaked nose
High arched palate
Cleft palate or bifid uvula
5% Pfeiffer 1
Crouzon-shallow orbits, significant proptosis
Normal intellect
Normal hands and feet
Acanthosis nigricans if FGFR3 mutation

"Mitten hands, feet" syndactyly bone and soft tissue
Thumbs broad, radially deviated
Rhizomelic shortening
Midline calvarial defect
50% have MR

Pfeiffer 1 (95%), 2 and 3
Variable brachydactyly
Broad, medially deviated thumbs and big toes
Type 2 has cloverleaf skull
Hydrocephalus, seizures, MR common


FGFR2-related acanthosis nigricans

Screen all patients with nonsyndromic coronal synostosis
Does not have distinctive facial features
Pro250Arg activating mutation

May be carpal or tarsal fusion
Thumbs normal
Big toes may be broad
Activating FGFR3 mutations
Paternal origin (age)
99% have G380R mutation
Most common disease-causing mutation in human genome

80% de novo
Inhibits chondrocyte proliferation

Thanatophoric dysplasia mutations
More strongly activating
Most common form of craniosynostosis
60% of nonsyndromic
is isolated saggital
1/5000 births
Males 3:1
Second most common form of craniosynostosis
Isolated coronal
20-30% of all nonsyndromic
1/10,000 births
Females predominate
What are the FGFR proteins?
Receptor tyrosine kinases
Dimerize when bind FGF

Gain of function mutations
Enhance dimerization
Enhance FGF binding
Make less specific for FGF
What is TWIST1?
Basic helix-loop-helix (bHLH)
transcription factor
Mesoderm differentiation

Causes Saethre-Chotzen syndrome
Autosomal dominant
TWIST happloinsufficiency
Coronal craniosynostosis
RasGap protein we know in a different disease?
50% de novo
Neurofibromin haploinsufficiency
Once Ras is activated, RasGaps turn it off

Regulates cell cycle progression

Mitogen-activated protein pathway
Puts the breaks on

Cancers: 10%
Malignant peripheral nerve sheath tumors
Pheochromocytoma, etc...

6 or more CAL >5mm prepubertal
(>15mm postpubertal)
Axial and inguinal freckling
Two or more neurofibromas of any type (85%)
Or one plexiform neurofibroma (15%)
Two or more Lisch nodules
Optic glioma
Tibial pseudarthrosis
Learning disabilities 50-75%
May have Noonan-like CV defects
Cardiovascular anomalies with Ras/MAPK pathway
Pulmonic stenosis
Aortic coarctation
Tetralogy of Fallot
Conotruncal defects
Mitral valve prolapse
EKG abnormalities
LV hypertrophy
Cardio-facio-cutaneous syndrome

Characteristic facial features
Earlobe creases
Deep philtrum, cupid's bow lip
Sparse, curly, fine hair
or Thick, WOOLY, brittle
ABSENT eyebrows and eyelashes
Heart defects
Skin hemangiomas, keratosis
Pigmented moles
Motor and speech delay
Learning disability in 100%
Ptosis, strabismus, nystagmus
Ventriculomegaly, hydrocephalus
NF1-like syndrome
SPRED1 haploinsufficiency
A negative regulator of Ras-Raf
Autosomal dominant

Cafe au lait macules
Axillary freckling
NS-like facies
Syndromes associated with neural tube defects
Most common syndromic cause
Renal cysts, hepatic duct dysplasia

Walker-Warburg Syndrome
Congenital muscular dystrophy
Spine rigidity
Ocular abnormalities

Waardenburg Syndrome
Autism >90%
Schizophrenia 90%
Bipolar disorder 90%
ADHD 80%
OCD 50%
Major depressive disorder 40%

Depression 10% pop
20% if sib with it
Autism causes
1/160 for ASD
Males predominate

90% idiopathic
10% can find a genetic cause

2-8% recurrence risk for sibs
When idiopathic
Very high heritability
Start with aCGH
Fragile X
Metabolic studies

Panels for X-linked intellectual disability
Neurexin (autosomal), Neurolignin (x-linked)

Fragile X (1-3% all autistic kids)
22q11.2 (20% have autism)
Tuberous sclerosis
MECP2 Rett syndrome
Maternal 15q DUPLICATION PW/Angelman critical region
(most common chromosomal reason)
1-3% of children with autism
Trisomy 21
PTEN with macrocephaly
Sotos syndrome
Timothy syndrome
16p11.2 deletions
Neonatal Marfan

Aged appearance
Valvular disease, severe progressive:
Mitral, tricuspid
Diaphragmatic hernia
Mitral valve disease
Polyvalvular disease
Neonatal Marfan
Trisomy 18