Luis Rohena, MD FAAP DABMG Assistant Professor of Pediatrics

Luis Rohena, MD FAAP DABMG
Assistant Professor of Pediatrics
Clinical Geneticist
March 28th and April 4th 2014
• 50% chance with each pregnancy child will be
Pedigree
Analysis
Autosomal
Dominant
affected
• Must show 3 generations and both genders
affected***
• Achondroplasia, Retinoblastoma, Marfan,
NF, Peutz Jegher, Waardenberg
• Will show unaffected parents w/ affected children
Pedigree
Analysis
• Affected parents likely to have “normal” children
• Children are obligate carriers
• Galactosemia, A-1-Antitrypsin, Sickle cell,
Cystic fibrosis, Wilson disease
Autosomal
Recessive
• Only women can pass this on
Pedigree
Analysis
• Look for affectegd men vs. affected women
passing on a condition
• If a man passing on the condition- can’t be
Mitochondrial
• Leber's hereditary optic atrophy
Mitochondrial
• No male to male transmission
Pedigree
Analysis
• Look for only males being affected
• Think of this in hx of uncles with a condition
• Hemophilia A/B**, G6PD def., Duchenne Muscular
Dystrophy, Wiskott- Aldrich, Fragile X**
X-Linked Recessive
• Look for an affected male who has affected
Pedigree
Analysis
daughters, not sons
• No male to male transmission
• Think of this in hx of uncles with a condition
• Alport, Aicardi, Vit D resistant rickets
X-Linked Dominant
• Prior to Pregnancy
Prenatal
Pediatrics
• 3 mos. prior recommended all women take:
• 400 mcg folic acid daily
• 4 mg daily if previously affected child
• Goal: Minimize incidence of neural tube defects,
cleft lip/palate?
• Maternal diabetes
• Cardiac anomalies
• CNS
• Caudal regression (Sirenomelia)
• Mermaid legs
• Preimplantation genetic diagnosis
• Ultrasound is important for accurate dates
Prenatal
Pediatrics
• If off by 7 days from LMP, do serial
measurements
• Fetal ultrasound
Non- Invasive
Prenatal
Monitoring
• Typically by 20 weeks
• As early as 12-16 weeks gestation
• Hydro/ anencephalus, myelomeningocele,
congenital heart defects, GI/GU abnormalities
• Can be seen as early as 16 weeks
• 1st Trimester Screen
• PAPP-A, HCG and measure nuchal translucency
• Between weeks 15 and 20 of pregnancy
Prenatal
Pediatrics
• Screen for levels of:
• Inhibin-A
• Alpha Feto Protein (AFP)
• B-HCG
• Estradiol
Quad Screen
2nd Trimester
Screening
• Increased AFP Assoc. with
• Open neural tube defects
• Abdominal wall defects
• Decreasd AFP Assoc. with
• Down syndrome (also high B-hCG and inhibin)
• Remember incorrect dates, multiple gestation can
affect results
Prenatal
Pediatrics
• CVS 10-12 weeks gestation
• Amniocentesis 16-20 weeks gestation
• Prenatal Umbilical Cord Blood Testing
Invasive Prenatal
Monitoring
• Done >19 weeks gestation
• Particularly useful in dx. of blood dyscrasias
• Measurement of phosphatidylglycerol
• Absent in amniotic fluid prior to 35 weeks GA
• The appearance of phosphatidylglycerol in the
amniotic fluid coincides with fetal lung maturity
(lecithin: sphingomyelin ratio)
• Most cases are due to errors in maternal
meiosis I
Prenatal
Pediatrics
• Recurrent risk for trisomy is approx. 1%
added to the mother’s age related risk
• At 22 y.o., a woman’s risk of Trisomy 21 is
Risk Assessment
for Trisomies
1: 1,500
• At 40 y.o., a woman’s risk of Trisomy 21 is
1: 90
• Always check parental karyotypes in children
with Trisomies
• Risk of parenatal balanced translocation
• Major factors:
• Duration of drinking
• Trimester when drinking
Teratogens
• There is no set associated quantity
• Pre- post natal growth deficiency
Alcohol
• Microcephaly
• Midface hypoplasia, short palpebral fissures, long
smooth philtrum, thin upper lip
• ASD/VSD
• Mental retardation
• Tremulousness
Teratogens
Alcohol
• Phenytoin, phenobarbital,
• Fingernail hypoplasia
• Cleft lip/palate
Teratogens
• Midface hypoplasia
• IUGR, hirsuite.
• Valproate
Antiepileptic
Drugs
• Neural tube defects
• Myelomeningocele
• Carbamazepine
• Fingernail hypoplasia
• 10 fold increase in neural tube defects
• Can look like Fetal Alcohol Syndrome, but no SGA or
microcephaly
Teratogens
Lithium
•
• Use for nodulocystic or severe inflammatory acne
• Potent teratogen
Teratogens
• CNS defects
• Hydrocephalus, microcephaly
• NOT meningomyelocele
• Conotruncal malformations
Isoretinoin
• Truncus arteriosus
• Microtia
• Severe nasal hypoplasia
Teratogens
• Laryngomalacia
• Can lead to airway obstruction
• CNS abnormalities
Warfarin
• Likely secondary to hemorrhage
• Severe mental retardation
• Stippling of epiphyses and vertebrae
• Hypoplastic distal phalange
• Heparin is safe for use
Teratogens
ACE Inhibitors
•
Teratogens
Smoking
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•
Teratogens
Matching
Coumarin
Microtia/anotia
ACE Inhibitors
Nail Hypoplasia
Hydantoin
Neural Tube Defects
Valproate
Stippling Epiphyses
Retinoic Acid
Renal Defects
Teratogens
Matching
Correct Answers
Coumarin
Stippling Epiphyses
ACE Inhibitors
Renal Defects
Hydantoin
Nail hypoplasia
Valproate
Neural Tube Defects
Retinoic Acid
Microtia/anotia
• Can detect abnormalities in chromosome
number or structural abnormalities
Genetics
• Get when there are three or more congenital
anomalies
• Assoc. with multiple congenital anomalies, growth
and mental retardation
Chromosome
Analysis
• Parental studies are needed if abnormality is
found
• Parental balanced translocation approx. 40%
chance risk of having another trisomic child
• Can detect translocations and inversions
• For microdeletion syndromes need FISH
Genetics
• DiGeorge syndrome
• Miller Dieker syndrome
• Prader-Willi and Angelman syndromes
• Can also be diagnosed on methylation studies
• Williams syndrome
FISH Studies
• Smith-Magenis
• Comparative Genomic Hybridization
• Replacing karyotype analysis
• Standard in diagnosis of microdeletions/
duplications
• Complete 1.8 million FISH analysis
• Malformation- Development of a structure is
arrested, delayed, or misdirected
• The consequence of multifactorial inheritance
Genetics
• Most common type of major anomaly observed in the
newborn infant
Malformations,
Sequences
and
Deformations
• Sequence- Occurs when a single developmental
defect results in a chain of defects
• Deformation- Due to mechanical forces acting on
a normal fetus
• Breech position, transverse lie, multiple gestations
oligohydramnios, malformed uterus
• Neurologic complications- hydrocephalus,
Genetics
Craniosynostosis
increased ICP- increased likeliness with 2
premature suture closures
Genetics
Craniosynostosis
Genetics
Deformations
Malformation
Sequence
• Usually happens prior to 12th week
gestation
• Any variety of malformations including
Amniotic Bands
amputation, clefts, constriction rings,
pseudosyndactyly
• Chorionic villus sampling can lead to
transverse terminal limb defects
•
Malformation
Sequence
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Potter Syndrome
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Renal agenesis
Cystic kidneys
Uteroplacental insufficiency
Amniotic Rupture
Malformation
Sequence
Pierre Robin
Sequence
Micrognathia
Posterior displacement of
tongue (glossoptosis)
Imaired closure of palatal
shelves
U-shaped or cleft palate
• Leads to posterior airway obstruction, can lead
to hypoxia, cor pulmonale, hypertension
• Associated with Stickler syndrome
• Autosomal dominant
• Hearing loss, myopia
Malformation
Sequence
Klippel Feil
Syndrome
Cervical vertebrae fused/ hemivertebrae 
secondary webbed neck
torticollis and facial
asymmetry
• Associated with hearing loss
• Congenital cardiac malformations
• Sprengal anomaly
• Congenital elevation of the scapula
•
Association
Sequence
VACTERL
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Association
Sequence
CHARGE
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Chromosomal
Abnormalities
Chromsosomal
Aneupoloidy
Chromosomal
Aneuploidy
•
Down Syndrome
th
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Chromosomal
Aneuploidy
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Down Syndrome
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•
Chromosomal
Aneuploidy
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Trisomy 13
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• Rocker bottom feet
Chromosomal
Aneuploidy
• Hypoplastic nails
• Horseshoe kidneys
Trisomy 18
• Clenched overlapping fingers
• Nail hypoplasia
• Cleft lip/palate
• Short sternum
• Ulnar deviation of hands
• Webbed neck
Chromosomal
Aneuploidy
• Cardiac anomalies
• Coarctation of the aorta, bicuspid aortic valve
• Prenatally have cystic hygroma
• Pterygium coli
• Newborn period have lymphedema
Turner Syndrome
• Short stature and delayed secondary sexual characteristics
• Estrogen replacement therapy at time of expected puberty
• Treat with growth hormone
• Cubitus valgus
• Horseshoe kidney
• Growth rate decreased between 3-12 yrs. Marked deceleration
afterwards.
Chromosomal
Aneuploidy
• 47, XXY
Chromosomal
Aneuploidy
• Marfanoid body habitus but usually not
dysmorphic until after puberty
•
Klinefelter
Syndrome
• Mild motor and developmental disabilities,
delayed speech, socially awkward
• Shy, poor self esteem
• Consider testosterone treatment
• Affect multiple genes where at least one is responsible for
the disorder
• Can also have a single gene defect
• Most of these are picked up by FISH
• No PATERNAL information
Microdeletion
Syndromes
Prader Willi
Syndrome
• Deletion of paternally-derived long arm of
chromosome 15 in 75%;
• Maternal uniparental disomy in 20%
• 15q11-13 deletion
• Cryptorchidism
• Small hands
• FTT first year of life- then obese
• Diagnosed on methylation studies
•
Microdeletion
Syndromes
No MATERNAL information
• 15q11-13 deletion
• Paternal uniparental disomy
Angelman
Syndrome
• Moderate severe Mental retardation
• Hand flapping
• Frequent laughter
• Ataxic gait
• Fair pigmentation
• Wide mouth
• Wide-spaced teeth
• Seizures
• 7q deletion
Microdeletion
Syndromes
• Elfin face
• Upturned nose
• Full lips
William syndrome
• Hypercalcemia
• Supravalvular aortic stenosis
• Good language development
• Cocktail party personality
• C- Cardiac anomalies
Microdeletion
Syndromes
• Tetralogy of Fallot
• A- Abnormal facies
DiGeorge
Syndrome
• T- Thymic Aplasia
• T-cell deficiency
• Check Immunoglobulins and T-cells
• C- Cleft lip/palate
• H- Hypocalcemia
• 22- 22q11.2 deletion
•
Microdeletion
Syndromes
Cri Du Chat
Syndrome
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• Hemihypertrophy
Microdeletion
Syndromes
• Gigantism
• Omphalocele
• Macrosomia,
Beckwith
Wiedemann
Syndrome
• Macroglossia
• Hypoglycemia- secondary to islet cell
hyperplasia
• Inc. risk for Wilms tumor and hepatoblastoma
• Monitor AFP’s q3months for first 4 years
• Monitor Abd US q3months for first 8 years
• Deletion 11p15
• Don’t be tricked by a female with Noonan Syndrome
Point Gene
Mutation
Noonan
Syndrome
• Autosomal dominant
• Coagulopathies
• Pulmonic stenosis, Cardiac hypertrophy
• Webbed Neck
• Pectus excavatum
• Low set ears
• Cryptorchidism
• Short stature
• Autosomal dominant
Point Gene
Mutation
• Aortic root dilitation
• Dolichocephaly
• Arm>Legs, Kypho/scoliosis
• +wrist, +thumb sign, Arachnodactyly
Marfan Syndrome
• Pes planus
• Marfan vs. Homocystinuria
• Homocystinuria
• Tx. Pyridoxine, diet high in cystine, low in
methionine
• Lens dislocation for Marfan: Anterior/Superior
• Homocysteinuria- Posterior/Inferior
• Autosomal dominant
Point Gene
Mutation
• Café au lait spots
• 50% spontaneous mutation rate
Neurofibromatosis
Type I
• Caused by mutation in NF tumor suppressor
gene
• Need to meet two of the criteria for diagnosis
• Of children with 6 or more café au laits, 90% will
meet diagnostic criteria in 3 years
• 6 or more café au lait spots
• (0.5 cm prepubertal; 1.5 cm post pubertal)
Point Gene
Mutation
Neurofibromatosis
Diagnostic
Criteria
• Axillary or inguinal freckling
• 2 or more Lisch nodules
• Optic glioma
• 2 or more neurofibromas
• Dysplasia of the sphenoid bone or thinning of
long bone cortex
• 1st degree relative with NF
• Autosomal dominant
Point Gene
Mutation
Tuberous
Sclerosis
• Hypomelanotic macule
• Cardiac rhabdomyomas
• Shagreen patches
• Ungual fibromas
• Cortical tubers, subependymal nodules,
seizures
• Facial angiofibromas
• Renal angiomyolipomas
Fragile X
Expansion
Repeat
Mutation
Point Gene
Mutation
• Male, mildly MR
• H/O males in family of lower than average
intelligence
• Large ears
• Increased testicular volume
• Dx. DNA expansion repeat analysis
Rett Syndrome
• X-Linked Dominant
• Autistic like behaviors
• Girls 1-2 y.o. regression
• Hand-wringing
• Progressive Microcephaly
• Autosomal dominant
Point Gene
Mutation
Osteogenesis
Imperfecta
• Abnormal function Collagen Type I
• Multiple fractures
• Hearing loss
• Blue sclera
• Lower extremity
bowing
• Autosomal Dominant
Point Gene
Mutation
• Mucosal hyperpigmentation
• Hamartomatous polyps of intestines
Peutz Jegher
Syndrome
• First presentation is onset Intussusception at
10-12 y.o.
• Increased risk of Cancers
• Pancreatic cancer
• Mammography at 25 y.o.
• Papanicolou annually
• Autosomal dominant
Point Gene
Mutation
• Malar hypoplasia
• Conductive hearing loss
Treacher Collins
Syndrome
• Micrognathia
• Lower eyelid coloboma
• Normal cognition
• Ear malformations/microtia
• Aniridia
Point Gene
Mutation
• Chromosome 11
• Think Wilms tumor
• Apert and Crouzon
• Craniosynostosis
• Syndactyly
• Diff b/w Apert and Crouzon- syndactyly with
Apert
• Autosomal dominant
Point Gene
Mutation
• Rhizomelic shortening
• Frontal bossing
Achondroplasia
• Macrocephaly
• Concern for atlantoaxial
instability
• Lumbar lordosis
• Nerve root compression
Caridac Lesion
Syndrome
Supravalvular AS
DiGeorge
Pulmonic Stenosis
Turner
Tetralogy of Fallot
Down
Complete AV Canal
Williams
Aortic Coarctation
Noonan
Matching
Supravalvular AS
Williams
Pulmonic Stenosis
Noonan
Tetralogy of Fallot
DiGeorge
Complete AV Canal
Down
Aortic Coarctation
Turner
Matching
• Very few questions and most are straightforward if you
know a few simple concepts
• Since the presentation is generally nonspecific, they will
try to trick you so read carefully (i.e. the septic-appearing
baby that is afebrile)
• Overt cardiopulmonary compromise
Metabolic
Disorders
Historical Clues
(tachypnea, apnea)
• Failure to thrive
• Developmental regression, hypotonia, seizures
• Mental status change- lethargy, coma
• Can often present with or like sepsis
• ALMOST all are autosomal recessive
• Fabry, OTC and Hunter are X-Linked
• Dysmorphic facial features
Metabolic
Disorders
• Cataracts or retinal pigmentary
changes
Physical
Examination
• Cardiomyopathy
• Progressive hepatosplenomegaly
• Hypotonia
• Unusual body or urine odor
• Disorders of carbohydrate metabolism
Metabolic
Disorders
Major Categories of
Metabolic Diseases
(galactosemia, glycogen storage
disease)
• Disorders of protein metabolism
(organic acidemias, amino
acidopathies, urea cycle defects)
• Disorders of fat metabolism (fatty acid
oxidation defects)
• Miscellaneous
(mucopolysaccharidosis,
lysosomal/lipid storage disorders, and
much, much more)
Fatty Acid Oxidation Disorder
Metabolic
Disorders
Hypoglycemia
With Fasting
• Inability to breakdown fat for energy utilization
• Lab Findings: Hypoglycemia w/ fasting, elevated
CK, +/- increased ammonia
• Tx. Avoid fasting, cornstarch
• No ketosis
Glycogen Storage Disease
• Inability to utilize glycogen for energy
• Lab Findings: Hypoglycemia, lactic acidosis,
elevated uric acid, hypertriglyceridemia,
neutropenia
• PE: Hepatosplenomegaly
• Dx. Liver biopsy, disease specific testing
• Tx. Avoid fasting, cornstarch
Von Gierkes- GSD I
Metabolic
Disorders
• Doll-like face, cherubic
• Hepatomegaly, seizures
• Labs:
• Increased triglycerides, CHL, lactic acid, uric
Glycogen Storage
Diseases
acid
• Neutropenia
• Tx. Tube feedings, cornstarch
Pompe Disease- GSD II
• Failure to thrive
• Cardiomegaly with high voltage on EKG
• Macroglossia,
•
Metabolic
Disorders
Hypoglycemia
With Feeding
• Presents once exposed to fruits
• 6-9 months
• + Reducing substances in urine/stool
•
• Defect in carbohydrate breakdown
• + Reducing substances in urine/stool
• Direct hyperbilirubinemia
• E. coli Sepsis
• Dx. galactose-1-phosphate uridyl
transferase enzyme assay
• Defect in amino acid breakdown
Metabolic
Disorders
• Lab findings:
• Anion gap metabolic acidosis
• Hyperammonemia
• Neutropenia
Organic
Acidemias
• Thromobocytopenia
• Isovaleric acidemia
Metabolic Acidosis
without increase in
Lactates
• Methylmalonic acidemia (MMA)
• Propionic Acidemia
• MMA can be B12 responsive
• Defect in amino acid breakdown
Metabolic
Disorders
Aminoacidopathies
• Milder presentation
• Labs: Anion gap metabolic acidosis,
normal ammonia level
Metabolic Acidosis
without increase in
Lactates
• Phenylketonuria
• Maple Syrup urine disease
• Homocystinuria
• Musty, mousy odor
Metabolic
Disorders
• Light pigmentation hair and skin
• If untreated:
• Severe MR
PKU
• Seizures
• Important to keep patient on phenylalanine
restricted diet, particularly during pregnancy
• If PKU + on NBS- refer to genetics
• Typically a mitochondrial oxidative
phosphorylation disorder
Metabolic
Disorders
• Use Lacatate/Pyruvate ratio
• 10: Pyruvate dehydrogenase deficiency
• 20: Normal
• >25 tissue hypoxia, pyruvate carboxylase
Mitochondrial
Metabolic
acidosis with
increase in
Lactates
deficiency, mitochondrial disorders
• Treatment:
• Riboflavin
• Coenzyme Q 10
• Thiamine
• Carnitine
• Treatment is empiric
Metabolic
Disorders
•
Urea Cycle
Defects
•
ABG
Elevated NH4
Normal NH4
Acidosis
Propionic A
MMA
FAOD
MSUD
Normal
Urea cycle
Aminoacidopathy
Galactosemia
Non ket hypergly
Metabolic
Acidosis
Metabolic
Disorders
Hurler Syndrome
• Corneal clouding
• Thickened skull
• Autosomal recessive
• Hepatosplenomegaly, progressive
deafness
Hunter Syndrome
• X-linked
• X Marks the Spot!!!
• Macroglossia, hepatosplenomegaly
• Progressive mental retardation
• Wilson
Metabolic
Disorder
• Jaundice, hepatomegaly
• Deposition of copper in the liver and brian
• No visual fdefects
• Ceruloplasmin levels are low, not diagnostic-
liver bx. is diagnostic
• Menkes Kinky Hair
• Low serum copper
• Lower serum ceruloplasmin (as in Wilsons
disease)- however tissue copper is high
Metabolic
Disorders
Enzyme Defect
Disorder
Glucose 6-phosphatase
Tay-Sachs
Iduronate-2-sulfatase
Hunter
Alpha-L-iduronidase
Von Gierke
Galactose-I-Phosephate
Uridyl Transferase
Hexosaminidase A
Hurler
Matching
Galactosemia
Metabolic
Disorders
Matching
Correct Answers
Enzyme Defect
Disorder
Glucose 6-phosphatase
Von Gierke
Iduronate-2-sulfatase
Hunter
Alpha-L-iduronidase
Galactose-I-Phosephate
Uridyl Transferase
Hurler
Galactosemia
HeXosaminidase A
Tay-SaXs
• Hypoglycemia + hepatomegaly + ketones =
glycogen storage disease
• Hypoglycemia - ketones = fatty acid oxidation
defect
Metabolic Key
Points
• Acidosis + normal lactate + ammonia =
organic acidemia
• Acidosis + normal lactate + normal ammonia =
amino acidopathy
•    ammonia - acidosis = urea cycle defect
•   lactate = mitochondrial disease
• Not heavily tested
• Don’t get caught up in minutia
• Approximately 15 questions, most are in picture section
• 1-2 Teratogens
• 2-3 Metabolic
• Know which heart lesions are associated with which syndromes
• Know the enzyme deficiencies associated with which metabolic
syndromes
• They love Turner syndrome and NF
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Anosmia
Bronze Skin
Self-Mutilation
High Pitched (cat) cry
Starburst Pattern to the Iris
Rhizomelic Shortening
Hand Wringing
Paucity of the Bile Ducts
Self Hugging
Exaggerated Startle Reflex
Heterochromia
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Kallmann Syndrome
Hemochromatosis
Lesch Nyhan Syndrome
Cri-du-chat
Williams Syndrome
Achondroplasia
Rett Syndrome
Alagille Syndrome
Smith Magenis Syndrome
Tay Sachs Disease
Waardenburg
• Questions, Questions, Questions
• Go through Laughing Your Way
• Supplement with Pediatric Board Review
• Zitelli
• Focus on small, colored boxes for key information
• Smith’s for major syndromes- Look at Pictures a couple days
before