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Board Review: Genetics. October 25, 2010. Major vs Minor Anomalies. Major: functional significance Polydactyly , colobomas , meningomyelocele , cleft lip Incidence 1\% Minor: cosmetic significance Epicanthal folds, single transverse palmar crease, supernumerary nipples Incidence 14\%

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Board Review:


October 25, 2010

major vs minor anomalies
Major vs Minor Anomalies
  • 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
question 1
Question 1
  • Pierre Robin is best described as a
    • A. Deformation
    • B. Disruption
    • C. Dysplasia
    • D. Sequence
    • E. 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
each of these can have an associated sequence
Each of these can have an associated sequence

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.

down syndrome
Down Syndrome


down syndrome major anomalies complications
Down Syndrome: Major Anomalies/Complications
  • 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
down syndrome14
Down Syndrome
  • Cognitive impairment
    • IQ 20-80
    • Mild to Moderate Developmental Delay
  • Early intervention, education, and sporting activities demonstrate improved outcomes.
  • Atlanto-axial instability
question 2
Question 2
  • 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. 2%
    • B. 15%
    • C. 33%
    • D. 50%
    • E. 100%
down syndrome17
Down Syndrome
  • 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
down syndrome maternal age
Down Syndrome: Maternal Age
  • Remember!!!!
    • Most children with Down Syndrome are NOT born to older parents!!!!
other trisomies
Other Trisomies
  • 13 (Patau) and 18 (Edwards)
    • May overlapping features!
    • Focus on characteristic features.
trisomy 13
Trisomy 13

P = Patau = Pits = Polydactyly

3 is a clefted 8

13= Midline defects

question 3
Question 3
  • 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. Karyotype
    • B. Progesterone and 17-hydroxyprogesterone
    • C. Microarray
    • D. FISH
    • E. Testosterone
turner syndrome
Turner Syndrome
  • 1/2000 liveborn females
  • Characteristics:
    • Primary amenorrhea
    • Sterility
    • Sparse pubic hair
    • Underdeveloped breasts
    • Short stature
    • Webbing of neck
    • Cubitusvalgus
    • Low hairline
    • Shield chest with wide spaced nipples
    • lymphedema
turner syndrome25
Turner Syndrome
  • 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
turner syndrome26
Turner Syndrome

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

question 4
Question 4
  • 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
klinefelter syndrome
Klinefelter Syndrome

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

klinefelter syndrome29
Klinefelter Syndrome
  • 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
question 5
Question 5
  • 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

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
fragile x35
  • 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
disorders of imprinting
Disorders of Imprinting



  • 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
prader willi infant
Prader-Willi Infant

Prader-Willi Toddler

  • Hypotonia resolves
  • Insatiable appetite
  • Obesity
  • Extreme tantrums
  • Markedly Hypotonic baby
    • May have decreased DTR
  • May be SGA
  • Poor feeding and FTT
  • Developmental Delay
prader willi child adult
Prader-Willi Child/Adult
  • 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

question 6
Question 6

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 axillaChoose the MOST likely diagnosis

A. Ehlers-Danlos

B. Infective endocarditis

C. Marfan syndrome

D. Rheumatic heart disease

E. Williams syndrome

connective tissue disorders
Connective Tissue Disorders
  • Avoid contact sports
    • Connective tissue (joint) injury
  • Marfan: Also avoid any strenuous exercise
    • Aortic dissection
marfan syndrome
Marfan Syndrome

AD- Fibrillin Gene

Normal intelligence = upward lens

Findings more obvious with aging

ehlers danlos
  • 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 hypertelorismare 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)
inborn errors of metabolism50
Inborn Errors of Metabolism
  • 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
smith lemli opitz syndrome
Smith-Lemli-Opitz Syndrome
  • AR
  • 1/20,000
  • Abnormal cholesterol biosynthesis
    • Block in the final step
    • Toxic precursors
      • 7-dehydrocholesterol
smith lemli opitz syndrome52
Smith-Lemli-Opitz Syndrome
  • 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
smith lemli opitz syndrome53
Smith-Lemli-Opitz Syndrome
  • Facial stigmata
    • Eyelid ptosis
    • Epicanthal folds
    • Strabismus
    • Low-set or posteriorly rotated ears
    • Broad nasal tip with upturned nares
    • Micrognathia
smith lemli opitz syndrome54
Smith-Lemli-Opitz Syndrome
  • 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
smith lemli opitz syndrome55
Smith-Lemli-Opitz Syndrome
  • Other Systems
    • Feeding problems
      • Failure to thrive
    • Heart
    • GI
    • Kidneys
  • Treatment
    • Oral cholesterol
      • Some improvement
question 7
Question 7

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 KetoticHyperglycinemia

E. Galactosemia

inborn errors of metabolism57
Inborn Errors of Metabolism
  • Infant with sudden onset of . . .
    • Lethargy
    • Vomiting
    • Tachypnea
    • Apnea
    • Irritability
    • Seizure
  • Preceding event . . .
    • feeding
inborn errors of metabolism58
Inborn Errors of Metabolism
  • Important questions
    • Acidosis or alkalosis?
    • Hyperammonemia?
    • Ketones with hypoglycemia?
Suspect Metabolic Disease

Increased Ammonia or Normal

Alkalosis or acidosis

See next slide

Urea Cycle Defects

Ketonuria or No ketonuria

  • OTC deficiency
  • Carbamoyl phosphate synthase deficiency
  • Citrullinemia
  • Argininosuccinicacidemia
  • Argininemia

Organic Acidemia

Fatty Acid Oxidation Defect

  • Propionic
  • Methylmalonic
  • Isovaleric
  • Glutaric
  • Maple syrup urine
  • MCAD
  • LCAD
inborn errors of metabolism60
Inborn Errors of Metabolism
  • Urea Cycle Defects
    • Plasma amino acids
  • Organic Acidemias
    • Urine organic acids
  • Fatty Acid Oxidation Defect
    • Plasma acylcarnitine profile
inborn errors of metabolism61
Inborn Errors of Metabolism
  • Galactosemia
  • Cataracts
  • Hyperbilirubinemia
  • Reducing substances
  • Hypoglycemia
  • Gram negative sepsis
  • Dx: GALT in RBCs
  • Non KetoticHyperglycinemia
  • Encephalopathy
  • Burst suppression on EEG
  • Difficult to control seizures

Normal ammonia

Clinical Differences

lysosomal storage diseases
Lysosomal Storage Diseases
  • 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
lysosomal storage diseases63
Lysosomal Storage Diseases










Tay Sachs

lysosomal storage diseases64
Lysosomal Storage Diseases
  • 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
lysosomal storage diseases66
Lysosomal Storage Diseases
  • Sphingolipidoses
    • Developmental regression
    • Organomegaly
    • Cherry red macula
    • Bone pain
    • Short
glycogen storage disease
Glycogen Storage Disease
  • 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
glycogen storage disease69
Glycogen Storage Disease
  • Pompe Disease (GSD II)
    • Cannot use muscle glycogen
    • Features
      • Muscle weakness
        • Muscles are hard
      • Rhabdomyolysis
      • FTT
      • Macroglossia
      • Cardiomegaly
    • Treatment
      • Enzyme replacement
question 8
Question 8

You suspect that a newborn may have VATER association. You can tell the parents that all of these findings are common EXCEPT:

  • Vertebral Anomalies
  • Anal Atresia
  • TE fistula
  • Mental retardation
  • Renal Anomalies
  • Facial Features
    • Wide-spaced, slightly down-slanting palpebral fissures, antevertednares, a short philtrum, small dysmorphic ears
  • Diagnosis
    • 4 of 6 criteria
    • One must be coloboma or choanalatresia
  • Inheritance - heterogeneous
  • May have clefts and/or renal abnormalities
  • May have agenesis or aplasia of thymus or parathyroids
    • Don’t confuse with DiGeorge!
  • Vertebral anomalies
    • Hemivertibrae, sacral abnormalitis
  • Renal
    • Unilateral agenesis, ectopic or horseshoe
  • Limb anomalies
    • Radial aplasia or hypoplasia, abnormal thumbs, preaxialpolydactyly, 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
cornelia de lange
Cornelia de Lange
  • 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
cornelia de lange79
Cornelia de Lange
  • 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
question 9
Question 9

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 valvularstenosis


E. AV canal

noonan syndrome
Noonan Syndrome
  • Autosomal Dominant
  • Similar to Turner
  • Chromosomal studies may be beneficial
  • 1/1000 to 1/2500
    • Males = Females
noonan syndrome82
Noonan Syndrome
  • Features
    • Webbing of neck
    • Sternal abnormalities - pectus
    • Pulmonicstenosis, hypertrophic cardiomyopathy
    • Coagulation abnormalities
    • Males
      • Cryptorchidisn
noonan syndrome83
Noonan Syndrome
  • 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
question 10
Question 10

A child exposed to alcohol during pregnancy is most likely to exhibit which of the following:

A. Neural Tube Defect

B. Tricuspid Atresia

C. Micropthalmia

D. Developmental Delay

E. Stippled epiphyses on x-ray of long bones

fetal alcohol syndrome
Fetal Alcohol Syndrome
  • 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
fetal alcohol syndrome87
Fetal Alcohol Syndrome
  • Newborns
    • SGA
    • Poor catch up growth
    • Hyper or hypotonia
    • Irritable or tremulous
  • Older children
    • Thin
    • Hyperactive
    • >80% developmental delay
      • Fine motor
anticonvulsant syndrome
Anticonvulsant Syndrome
  • 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
  • Truncusarteriosis
  • Absent thymus
warfarin embyopathy

ACE Inhibitors

Depressed nasal bridge

Short nose

Hypoplastic distal phalanges

Stippled epiphyses



Hypoplasia of the skull

mitochondrial disorders
Mitochondrial Disorders

Disorder of energy metabolism

Lactic acidosis often seen

All mitochondria are inherited from Mom