Transcript Major vs Minor Anomalies

Board Review:
Genetics
October 25, 2010
 Major: functional
significance
• Polydactyly, colobomas, meningomyelocele, cleft
lip
• Incidence 1%
 Minor: cosmetic
significance
• Epicanthal folds, single transverse palmar
crease, supernumerary nipples
• Incidence 14%
 Both
more common in premature babies
 Pierre
• A.
• B.
• C.
• D.
• E.
Robin is best described as a
Deformation
Disruption
Dysplasia
Sequence
Association
 Broad
term
 An abnormality of embryonic
morphogenesis
 Usually results from genetic,
chromosomal, or teratogenic influences
• May be multifactorial
 Constitutes
single primary defect
 OR, component of multiple malformation
syndrome
 Often require surgical intervention
 Alteration
(often molding) of intrinsically
normal tissue due to exposure of unusual
extrinsic forces.
• Uterine constraint from crowding
• Potter facies
 Most
respond to medical therapy and
have good prognosis
 Breakdown
of normally formed tissue
 Vascular accidents
 Amniotic bands
 Earlier in embryogenesis: More severe
 Abnormal
organization
of cells within tissue
 Genetic basis
 Achondroplasia
• Most frequent cause of
skeletal dysplasia
Malformation: Embryonic morphogenesis
Deformation: Alteration of intrinsically normal tissue by external
force
Disruption: Breakdown of normally formed tissue
Dysplasia: Abnormal organization of cells within tissue
 Single
problem in morphogenesis
 Cascade resulting in series of
structural alterations
• Recognizable pattern of multiple
anomalies
 Pierre
Robin
• Microretrognathia (single, primary
malformation)
 Glossoptosis: posterior placement of tongue
 U-shaped cleft palate
 Pattern
of malformations that occurs
together too frequently to be due to
random chance.
 No specific etiology is known.
Nonspecific
 Congenital heart disease (45%)
• AV Canal Defects
 GI anomalies (5%)
• Duodenal atresia
• Hirschsprung
 Thyroid disorders
• ! Regular Screening !
 Leukemia
• 15 to 20 times more common
• Neonates may have transient leukemoid reaction
 Cognitive
impairment
• IQ 20-80
• Mild to Moderate Developmental Delay
 Early
intervention, education, and
sporting activities demonstrate improved
outcomes.
 Atlanto-axial instability
A
parent of a child with Down Syndrome
is found to have a 21/21 translocation.
What are the chances that her next child
will have Down Syndrome?
• A.
• B.
• C.
• D.
• E.
2%
15%
33%
50%
100%
 If
either parent has 21/21 translocation
• All children will have Down Syndrome
 If
parent has 21/centric translocation
• 2% of father’s children
• 15% of mother’s children
Maternal Age
Prevalence
25
1/1350
35
1/355
45
1/23
 Remember!!!!

Most children with Down Syndrome are NOT
born to older parents!!!!
 13
(Patau) and 18 (Edwards)
• May overlapping features!
• Focus on characteristic features.
P = Patau = Pits = Polydactyly
3 is a clefted 8
13= Midline defects
8
8
A
15-year-old girl comes to your office because
she never has had a menstrual period. She has no
chronic illnesses and is active playing softball
once a week. Her mother and sister both had
menarche at age 13 years. On physical
examination, she is at the 15th percentile for
height and weight and has no hirsutism or acne, no
breast development, and Sexual Maturity Rating 3
pubic hair development.
 The MOST appropriate lab test is:
•
•
•
•
•
A.
B.
C.
D.
E.
Karyotype
Progesterone and 17-hydroxyprogesterone
Microarray
FISH
Testosterone


1/2000 liveborn females
Characteristics:
Primary amenorrhea
Sterility
Sparse pubic hair
Underdeveloped breasts
Short stature
Webbing of neck
Cubitus valgus
Low hairline
Shield chest with wide spaced
nipples
• lymphedema
•
•
•
•
•
•
•
•
•
 Other organ systems
• Renal anomalies
• Congenital heart disease
 Bicuspid aortic valve (30%)
 Aortic coarctation (10%)
 Mental development usually
normal
 Findings may be subtle and missed until
adolescence
• Get karyotype on adolescent female with
delayed puberty, especially if short stature
 Karyotype
45X
 Recurrence risk for parents is 1-2%
unless a parent has abnormal X
 15% are Mosaics
 If mosaic has an XY cell line, gonads
should be removed
 Does
the risk of having a child with
Turner Syndrome or Klinefelter
Syndrome increase with advanced
maternal age?
• A. Yes for both
• B. No for Turner, Yes for Klinefelter
• C. Yes for Turner, No for Klinefelter
• D. No for both
 1/500
newborn boys
 Physical stigmata may not be obvious
until puberty
 Testosterone levels usually low (variable)
 IQ is normal (or mildly decreased)
 Behavioral problems may be more
common
 Karyotype
• XXY 80%
• XY/XXY in 20%
 IF
additional X present (XXXY)
• More cognitive and skeletal abnormalities
 Congenital
Heart Disease may be seen
• PDA most common
 Parents’ recurrence
risk 1-2%
 Risk increases with maternal age
Klinefelter
A
new 13 year old male patient has a long,
narrow face and enlarged, protruding ears, and
joint laxity. He is very active, has difficulty
making eye contact, and engages in some hand
flapping. His most recent testing showed an IQ
of 45. Family history reveals that the maternal
uncle has intellectual disability.

The MOST appropriate test to confirm the diagnosis is
• A. Karyotype
• B. Skin biopsy for staining
• C. Molecular DNA analysis
• D. MRI of Brain
• E. Clinical Diagnosis Only
 There
is an excess of males in the
mentally retarded population
 This is largely due to Fragile-X
 Most
common chromosomal cause of MR
 May be expressed (less severe) in females
 Expression may be amplified over
generations (anticipation)
 Physical
•
•
•
•
•
•
Long face
Long, protruding ears
MR
Prominent jaw
Macroorchidism
May have hyper-extensible joints
 Trinucleotide
repeat disorder
 Inheritance X-linked Dominant
• Variable expressivity
• Expression amplified over generations
 Look
for Hx of affected male family
members (uncles)
 Choose molecular DNA analysis
• Methylation study
• Otherwise PCR or Southern Blot
Angelman
Prader-Willi
 Function
of certain genes is dependent
on their parental origin
• Maternal vs Paternal
• Particularly for 15q11-13
 Prader-Willi
• Deletion of paternally derived Chromosome 15
 Angelman
• Deletion of maternally derived Chromosome 15
 Diagnosis: Methylation, High-resolution
cytogenetics, or FISH
 Markedly
Hypotonic baby
• May have decreased DTR
 May
be SGA
 Poor feeding and FTT
 Developmental Delay
 Hypotonia
resolves
 Insatiable appetite
 Obesity
 Extreme tantrums
 Diabetes
Mellitus
 Slipped Capital Femoral Epiphysis
 Limited life expectancy
• Cardiorespiratory complications
 Pickwickian syndrome
 AKA (Obesity hypoventilation)
 Skin
picking
 Severe
cognitive deficits
 Speech impaired or absent
 Inappropriate paroxysms of laughter
 May have ataxia and seizures

You evaluate a 16-year-old varsity volleyball player.
The girl's height is 71 inches, weight is 125 lb, and
blood pressure is 115/74 mm Hg. You note scoliosis
and a 3/6 holosystolic murmur heard at the cardiac
apex with radiation to the left axilla
Choose the MOST likely diagnosis





A.
B.
C.
D.
E.
Ehlers-Danlos
Infective endocarditis
Marfan syndrome
Rheumatic heart disease
Williams syndrome
 Avoid
contact sports
• Connective tissue (joint) injury
 Marfan: Also
avoid any strenuous
exercise
• Aortic dissection
 AD-
Fibrillin Gene
 Normal intelligence = upward lens
 Findings more obvious with aging
 Mostly
AD
 Defect of collagen
 Fragil “velvety” skin
• “Cigar Paper”
• Scar formation
• Impaired wound healing
• Use glue or tape
 Beals
Syndrome
• Abnormal fibrillin 2
• Tall, arachnodactyly
• Broad forehead and hypertelorism are distinct
features
 Homocystinuria
• Error of methionine metabolism
• Tall, thin habitus, scoliosis, pectus
 Distinctive
features:
• Inferiorly displaced lens
• Hypercoaguability
• Mental retardation
 Treatment
• May respond to B6 (pyridoxine)
 Altered
or abnormal gene that codes for
the production of an abnormal product
• Enzyme or cofactor needed for metabolic
process
 Cannot
make end-product
• Abnormal structure and function
• Increased precursors
 AR
 1/20,000
 Abnormal
cholesterol biosynthesis
• Block in the final step
• Toxic precursors
 7-dehydrocholesterol
 Clinical features
• Pregancy
 SGA
 Decreased fetal movement
 Breech
• Abnormal CNS development
 Microcephaly
 Prominent occiput
 Narrow bifrontal diameter





Seizures
Hypotonia then hypertonia
Irritable behavior
Shrill screaming
MR
 Facial
stigmata
• Eyelid ptosis
• Epicanthal folds
• Strabismus
• Low-set or posteriorly
rotated ears
• Broad nasal tip with
upturned nares
• Micrognathia
 Clinical Features
• Simian crease
• Syndactyly of 2nd and 3rd toes
• Hypospadias with cryptorchidism
• Ambiguous genitalia
 Less common
• Clenched hands
• Digital abnormalities
• Cataracts
• Cleft palate
• Bifid uvula
 Other
Systems
• Feeding problems
 Failure to thrive
• Heart
• GI
• Kidneys
 Treatment
• Oral cholesterol
 Some improvement
A 14 month old female presented with developmental
delay to your clinic. The patient has been pulling to
stand but lost this ability and seems to be regressing
in overall development. Late in infancy, the parents
noticed gradual changes in craniofacial features
including prominence of forehead. On exam, you
notice frontal bossing, cloudy cornea, HSM and stiff
elbows. The patient most likely has a disorder within
which category of inborn error of metabolism?
A. Lysosomal Storage Disease
B. Glycogen Storage Disease
C. Organic Acidemia
D. Non Ketotic Hyperglycinemia
E. Galactosemia
 Infant
with sudden onset of . . .
• Lethargy
• Vomiting
• Tachypnea
• Apnea
• Irritability
• Seizure
 Preceding
• feeding
event . . .
 Important
questions
• Acidosis or alkalosis?
• Hyperammonemia?
• Ketones with hypoglycemia?
Suspect Metabolic Disease
Increased Ammonia or Normal
Alkalosis or acidosis
Urea Cycle Defects
•OTC deficiency
•Carbamoyl
phosphate
synthase
deficiency
•Citrullinemia
•Argininosuccinic
acidemia
•Argininemia
See next slide
Ketonuria or No ketonuria
Organic Acidemia
•Propionic
•Methylmalonic
•Isovaleric
•Glutaric
•Maple syrup urine
Fatty Acid Oxidation
Defect
•MCAD
•LCAD
•VLCAD
 Urea
Cycle Defects
• Plasma amino acids
 Organic
Acidemias
• Urine organic acids
 Fatty
Acid Oxidation Defect
• Plasma acylcarnitine profile
 Normal
ammonia
 Clinical Differences
Galactosemia
Non Ketotic
•Cataracts
Hyperglycinemia
•Hyperbilirubinemia
•Encephalopathy
•Reducing substances •Burst suppression on
•Hypoglycemia
EEG
•Gram negative sepsis •Difficult to control
•Dx: GALT in RBCs
seizures
 Mutation
in gene coding for production
of lysosomal enzymes
• Accumulation of substrate
• Impairment of cell function
 >40
different LSD
 Start
in late infancy or early childhood
with slowly progressive symptoms
Mucopolysaccharides
Glycolipids
Hurler’s
Hunter’s
Sanfilippo
Morquio
Gaucher
Fabry
Krabbe
Tay Sachs
 Mucopolysaccharidoses
• Cannot break down
glycosaminoglycans
• Clinical effects
 Coarsening of facial features
 Skeletal abnormailities
 Dysostosis multiplex




Joint structure and function
Organomegaly
+/- Cognitive abilities
+/- Corneal clouding
• Treatment: enzyme
replacement or BMT
Disease
Description
Inheritance
Hurler’s (MPS I)
+ corneal clouding
+ developmental
regression
AR
Hunter’s (MPS II)
no corneal clouding
+ developmental
regression
X-linked
Sanfilippo (MPS III)
no corneal clouding
+ developmental
regression
AR
Morquiro (MPS IV)
+ corneal clouding
* Normal intelligence
AR
 Sphingolipidoses
• Developmental regression
• Organomegaly
• Cherry red macula
• Bone pain
• Short
Disease
Description
Gaucher
HSM, bone pain, easy bruisibility
Fabry
Orange-colored skin lesions, opacities
of the eye, vascular disease (heart,
brain, kidney)
Krabbe
Demyelination and progressive neuro
deterioration
Tay Sachs
No HSM, cherry red spot, neuro
deterioration
Niemann-Pick
HSM, cherry red spot
 Von
Gierke Disease (GSD I)
• Liver can’t produce glucose
• Features
 Hypoglycemia with prolonged fasting
 Organomegaly
 Cherubic face
 Poor growth
 Elevated TG and cholesterol
• Lab findings
 Elevated lactic and uric acid
• Treatment
 Frequent snacks and meals
 Pompe Disease (GSD II)
• Cannot use muscle glycogen
• Features
 Muscle weakness
 Muscles are hard
 Rhabdomyolysis
 FTT
 Macroglossia
 Cardiomegaly
• Treatment
 Enzyme replacement
You suspect that a newborn may have
VATER association. You can tell the
parents that all of these findings are
common EXCEPT:
A.
B.
C.
D.
E.
Vertebral Anomalies
Anal Atresia
TE fistula
Mental retardation
Renal Anomalies
C
Coloboma of retina (or iris)
H
Heart abnormalities
A
Atresia of the choanae
R
Retarded growth and mental
development
G
Genital hypoplasia in males
E
Ear anomalies (hearing loss)

Facial Features
• Wide-spaced, slightly down-
slanting palpebral fissures,
anteverted nares, a short
philtrum, small dysmorphic ears

Diagnosis
• 4 of 6 criteria
• One must be coloboma or
choanal atresia
Inheritance - heterogeneous
May have clefts and/or renal
abnormalities
 May have agenesis or
aplasia of thymus or
parathyroids


• Don’t confuse with DiGeorge!
V
Vertebral anomalies
A
Anal anomalies
+/- C
Congenital Heart Disease (VSD)
T
Tracheoesophageal fistula
E
Esophageal atresia
R
Radial and/or renal abnormalities
+/- L
Limb defects
 Vertebral anomalies
• Hemivertibrae, sacral
abnormalitis
 Renal
• Unilateral agenesis,
ectopic or horseshoe
 Limb anomalies
• Radial aplasia or
hypoplasia, abnormal
thumbs, preaxial
polydactyly, syndactyly
 Etiology
• Unknown
 Normal intelligence
 Must
get a karyotype to rule out
chromosomal disorders
 Townes-Brocks
• Similar to VATER
• Autosomal Dominant
• Ear, thumb and anal abnormalities
 No vertebral anomalies or TE fistula

Features
• IUGR
• FTT
• Moderate to severe cognitive
•
•
•
•
impairment
Microcephaly
Flat occiput
Low posterior hairline
Facial Features
 Long eyelashes, synophrys, small
upturned nose with anteverted nostrils,
long philtrum, downturned upper lip
with cupid’s bow shape and
micrognathia
• Small hands and feet

Features cont. . .
•
•
•
•
•
•
•
Proximally placed thumbs
Flexion contractures of elbows
Hypoplastic limbs
Phocomelia
Hirsutism
Cutis marmorata
Males
 Hypospadias and cryptorchidism
• Females
 Bicornate uterus

Autosomal dominant
• Most cases are new mutations
What is the most common heart defect
seen in patient’s with Noonan Syndrome?
A. Supravalvular aortic stenosis
B. Coarctation of the aorta
C. Pulmonary valvular stenosis
D. VSD
E. AV canal
 Autosomal
 Similar
Dominant
to Turner
 Chromosomal
 1/1000
studies may be beneficial
to 1/2500
• Males = Females
 Features
• Webbing of neck
• Sternal abnormalities - pectus
• Pulmonic stenosis,
hypertrophic cardiomyopathy
• Coagulation abnormalities
• Males
 Cryptorchidisn
 Features
• Facial features
 Widely spaced eyes with
down-slanting palpebral
fissures, ptosis,
retrognathia, low set,
posteriorly rotated ears,
coarse, curly hair with low
hairline
• Delayed puberty
• Short-stature
• Normal intelligence
A child exposed to alcohol during
pregnancy is most likely to exhibit which
of the following:
A.
B.
C.
D.
E.
Neural Tube Defect
Tricuspid Atresia
Micropthalmia
Developmental Delay
Stippled epiphyses on x-ray of
long bones
 No
amount of alcohol is safe in
pregnancy!
 Features
•
•
•
•
•
•
•
Microcephaly
Pre and post natal growth deficiency
Short palpebral fissures
Long, smooth philtrum
Thin upper lip
Short nose
Hypoplasia of nails and distal
phalanges
 Newborns
• SGA
• Poor catch up growth
• Hyper or hypotonia
• Irritable or tremulous
 Older
children
• Thin
• Hyperactive
• >80% developmental delay
 Fine motor
Phenytoin, phenobarbital,
carbamazepine
 Features

• Microcephaly
• IUGR
• Facial Features
 Broad nasal bridge, small anteverted
nostrils, long upper lip
• Fingernail hypoplasia
• Heart defects
• Hypospadias with cryptorchidism
• Clubfoot
• Valproic Acid
 NTD
 Ebstein’s anomaly
• Tricuspid atresia
 Microcephaly
 Micropthalmia
 Hypoplastic
ears
 Truncus arteriosis
 Absent thymus
 Depressed
nasal bridge
 Short
nose
 Hypoplastic distal phalanges
 Stippled epiphyses
 Anuria
 Oligohydramnios
 Hypoplasia
of the skull
 Disorder
of energy metabolism
 Lactic acidosis often seen
 All mitochondria are inherited from Mom
M
Mitochondrial
M
Mitochondrial
E
Encephalopathy
E
Encephalopathy
L
Lactic
R
Ragged
A
Acidosis
R
Red
S
Stroke
F
Fibers
N
Neuropathy
A
Ataxia
R
Retinitis
P
Pigmentosa