GOAL

1
GOAL

• To understand important genetic principles and
  disorders in the context of a common pediatric
  problem
• Developmental Delay and Mental Retardation

2
Diagnostic Categories of Severe Mental
Retardation

• FSIQ lt50 0.3-4 of population
• 10-20 of those with MR
• relevant to children surviving at least one year
• Cause is apparent for about 50
• Chromosomal abnormalities or
  35 Mendelian single gene disorders
• Multiple congenital anomaly syndromes
• or isolated brain malformation
  20
• Perinatal causes (or presumed)
  15
• Environmental
  5
• Congenital infections
  5
• Unknown
  20

3
Diagnostic Categories of Mild Mental Retardation

• IQ 50-70 prevalence 0.5-3marked
  influence of socioeconomic status
• Cause is apparent for about 50
• Chromosomal abnormalities or 5
  Mendelian single gene disorders
• Multiple congenital anomaly syndromes 10
• Pregnancy complications
  15
• Environmental
  10
• Unknown Cultural/familial
  50

4
Causes of Mental Retardation or Developmental
Delay

• Chromosomal
• Mendelian single gene disorders
• Autosomal dominant inheritance
• Microdeletions
• Imprinting
• Autosomal recessive inheritance
• Inborn errors of metabolism
• X-linked inheritance
• Triple nucleotide repeat diseases
• Environmental

5
Trisomy 21 important facts

• 1600 birth prevalence
• maternal age-dependent risk
• MSAFP screening programs can potentially detect
  about 2/3 of cases at 16-18 weeks
• Cardiac malformations about 50echo every
  patient
• 12-20 atlanto-occipital instabilitysymptoms of
  cord compression rare change bowel or bladder
  function, neck posturing, loss of ambulatory
  skills
• hypothyroidism
• 5 duodenal atresia
• lt1 leukemia

6
Trisomy 21 important facts

• 94 trisomy 21
• origin of extra 21 is maternal 90
• 2.5 mosaic with normal cell line
• 3.5 translocation Down syndrome
• Recurrence risks
• If trisomy 21, maternal age at next pregnancy
  determines risk
• Translocations (mostly 14/21)
• 10-14 mothers
• 2 fathers

7
Trisomy 21 diagnostic aids

• Facies epicanthal folds, flat midface,
  protruding tongue, thrustingsingle palmar
  creases
• Hypotonia -- nearly all
• Small ear height (lt3)
• Mild limb shortening
• Nuchal fat pad
• Brushfield spots on irides
• Speckled ring at 2/3 width of iris
• Theatrical grimace

8
Trisomy 21 - outcomes

• Delayed major motor milestones partly due to
  hypotonia clumsy later ages
• Delayed language acquisition
• Wide range of intellectual functioningmean IQ 50
  but falls by adolescence
• Social performance is better

9
Trisomy 18 features

• IUGR feeble neonates
• Facies triangular, small mouth
• Lowset, malformed ears
• Clenched hands with overlapping fingers
• Rocker bottom feet
• Short sternum
• Cardiac defects 90

10
Trisomy 18 important facts

• Frequency 15000
• Often multiple organ system involvement
• Median survival only 5 days
• MR profound, with only 10 survival to 1 year

11
Trisomy 13 phenotypic features

• Facial features bulbous nasal tip, cleft lip ?
  cleft palate, microphthalmia
• Scalp defects
• Postaxial (ulnar side) polydactyly
• Cardiac defects - high percentage VSD,ASD,
  transposition of the great arteries
• Brain malformations - esp holoprosencephaly

12
Trisomy 13 - facts

• Birth prevalence 17000
• Characteristic major and minor anomalies
• Survival rare
• Profound MR

13
Microdeletion disorders

• Most of the time, these microdeletions are too
  small to be cytogenetically visible
• Concept of contiguous gene disorder
• Prader-Willi and Angelman syndromes
• Velo-cardio-facial syndrome
• Williams syndrome
• Duchenne muscular dystrophy

14
FISH analysis for detecting microdeletions

• FISH fluorescent in situ hybridization
• A fluorescently labelled DNA probe is allowed to
  hybridize to the DNA sequence to which its base
  pair sequence is homologous
• In a normal subject, the probe will hybridize to
  each of a gene pair (eg., each 15 chromosome)
• If the subject has a microdeletion, then there is
  only one homologous DNA sequence to which the
  fluorescent probe can hybridize
• This technique can also be used to identify extra
  (duplicated) chromosomal material

15
Prader-Willi syndrome features

• Decreased fetal activity
• Moderate/severe neonatal hypotonia
• Poor feeding often FTT early
• Obesity usually does not begin until they can
  gain access to food on their own hiding food,
  stashing food, stealing food
• Obesity accompanied by short staturemore likely
  to see tall stature with overfeeding
• Hygonadism
• Tapering fingers
• MR mild gt90
• Behavioral phenotype skin picking enjoy doing
  puzzles food seeking behaviors

16
Prader-Willi syndrome

• Two main mechanisms of inheritance
• 70 microdeletion 15q11-13
• deletion is always on paternal 15
• 30 uniparental disomy for chromosome 15
• disomy always for maternal 15
• rarely due to imprinting
  abnormality
• uniparental disomy one parent contributes two
• copies of a chromosome and the other
  parent
• contributes none
• lab diagnosis by DNA testing for SNRPN gene
• (methylation analysis) or by FISH

17
Genomic imprinting

• For certain genes, functional status depends upon
  the parent of origin (differential expression)
  and only one copy of the gene is functional
• in other words, only the maternally derived
  copy of the gene, or only the paternally derived
  copy, may be functional
• One mechanism of imprinting appears to be
  methylation of the gene or its control regions
• Imprinting state is wiped clean during oogenesis
  and spermatogenesis and a new pattern of
  imprinting is determined

18
Angelman syndrome

• 115,000
• Two main mechanisms of inheritance
• microdeletion 15q11-13
• deletion is always on maternal 15
• 5 uniparental disomy for chrom 15
• disomy always for paternal 15
• lab diagnosis by DNA testing for SNRPN gene
  (methylation analysis) or by FISH

19
Angelman syndrome features

• MR severe
• Often little or no speech development
• Unprovoked laughter and squealing
• Ataxia, stiff gait, upper limbs held like a
  marionette
• Seizures, very commonusually with onset in
  infancy
• Facial features evolve over time

20
Velo-cardio-facial (VCF) syndrome

• Frequency uncertain 1-/3-4000 live births
• Microdeletion 22q11
• Probably mutliple genes cause phenotype
• 86 have large 3 MB deletion
• Highly variable phenotype, even among family
  members with the same deleted segment
• Autosomal dominant inheritance
• Parents of affected children should be tested
• 6 of cases have affected parent
• Diagnosis by FISH testing

21
Velo-cardio-facial syndrome features

• Most cases identified by cardiac defect, cleft
  palate, or hypernasal speech
• Cardiac defects 11 of conotruncal defects
• Tetralogy of Fallot, high subaortic VSD, truncus
  arteriosus, d-transposition, retroesophageal R
  subclavian, double outlet R ventricle, pulmonary
  atresia with VSD, interrrupted arch type b
• DiGeorge anomaly complex 80 of cases
• T-cell deficiency
• hypoparathyroidism

22
Velo-cardio-facial syndrome features

• Cleft palate or submucous cleft palate
• VPI , hypernasal speech
• Characteristic facies
• tubular nose mildly hypotonic facies
• Developmental delay (mainly language), learning
  disabilities, mild-moderate MR, behavioral
  problems
• Psychiatric disorders -- onset rare before
  mid-late teen years
• may be as frequent as 25
• Many other reported associations

23
Williams syndrome

• Microdeletion 7q
• deletion of the elastin gene
• Diagnosis by FISH

24
Williams syndrome - features

• Facies Elfin
• Changes over time, get coarser
• Prominent lips, short palpebral fissures
• Stellate irises
• Hypercalcemia generally limited to infancy
• uncommonly detected, and resolves at variable
  ages
• Irritable infants, poor feeding
• Cardiac defects - supravalvular aortic
  stenosis
• Pulmonic stenosis hypertension!
• Hoarse voice
• Characteristic personality, learning problems
• Very musically inclined, sensitive to noises

25
Duchenne muscular dystrophy

• X-linked inheritance pattern
• Caused by abnormal dystrophin or absent protein
• Diagnostic testing
• FISH for microdeletion
• Mutation analyses for missing exons
• Point mutation analyses
• Muscle bx --stain for dystrophin

26
Duchenne muscular dystrophy features

• Vague onset of clumsiness, not keeping up with
  peers, before age 5
• Calf pseudohypertrophy
• Elevated creatine kinase, begins well before
  signs of weakness appearsometimes CK elevated
  in female carriers
• Waddling gait, toe walking
• Gower sign signifies proximal weakness,
  which is progressive and then distal weakness
  appears later
• About 25 have subnormal IQ or mild MR
• Usually confined to wheelchair by 10-11 years
• Death usually late teens to early 20s

27
Beckwith-Wiedemann syndrome - features

• Hydramnios prematurity
• Overgrowth syndrome
• Macroglossia
• Macrosomia
• Neonatal hypoglycemia
• Hemihypertrophy
• Large kidneys, nephroblastomatosis
• Omphalocele
• Face glabellar hemangioma, ear lobule creases
• Cleft palate
• Advanced bone age

28
Beckwith-Wiedemann syndrome Genetic
heterogeneity

• 1. 11p15 duplications 1
• parent of origin always paternal
• 2. 11p15 translocations rare
• parent of origin always maternal
• 3. uniparental disomy 11p
• parent of origin always paternal
• 10-20 of sporadic cases
• may only find on tissue culture
• somatic mosaicism for 11p15 also seen in isolated
  hemihypertrophy Wilms tumor
• IGFR2 normally only expressed from paternal 11p
  biallelic expression in B-W S

29
Beckwith-Wiedemann syndrome Genetic
heterogeneity

• 4. mutations of p57KIP2 gene
• 10 of cases
• most mutations truncate the protein
• an imprinted gene
• Summary
• 1 chromosome abnormality
• 20 uniparental disomy
• 10 p57KIP2 mutations
• most cases involve imprinting abnormality of
  unknown type

30
Fragile X mental retardation

• X-linked inheritance
• Common cause of MR
• 11250 males 12000 females
• 6 of retarded males 0.3 of retarded females
• maintain high index of suspicion because of
  implications for extended family
• mechanism of mutation unstable expansion of
  trinucleotide repeat when expansion exceeds a
  limit, gene is methylated and no protein is made
• diagnostic testing
• quantitation of of trinucleotide repeats
• not all affected people have cytogenetic fragile
  sites

31
Fragile X Mental Retardation

• Phenotype
• Males large ears, large testicles rarely is
  apparent before puberty, hyperextensible,
• Overgrowth, coarse facies with age
• autism
• Females shy, poor social skills
• Learning disabilities
• Range of intellectual functioning

32
Neurofibromatosis -- NF1

• Common AD disorder 13000
• 50 due to new mutations
• Highly variable expressivity
• Most (about 2/3) have problems limited to skin
• AD isolated café-au-lait spots is rare
• 1/3 have more serious problems
• genetic testing detects 60-70 of those who meet
  the diagnostic criteria
• very large gene, encodes neurofibromin
• GTPase activating protein
• protein truncation assay detects mutations that
  result in prematurely terminated protein

33
Neurofibromatosis -- NF1

• Autosomal dominant inheritance
• NIH consensus clinical diagnostic criteria
• Must have two or more from this list
• 1. 6 or more café-au-lait spots
• ? 5mm before puberty ? 15mm after
  puberty
• 2. axillary/inguinal freckling
• 3. 2 neurofibromas or 1 plexiform neurofibroma
• 4. 2 or more iris Lisch nodules
• 5. optic glioma
• 6. tibial pseudoarthrosis or sphenoid dysplasia
• 7. affected 1st degree relative

34
Neurofibromatosis -- NF1

• Most common referral is for assessment of café-
  au-lait spots
• Other diagnostic clues
• Large head
• Learning problems 30-50
• 90 adults have Lisch nodules
• Monitor for complications
• Skeletal
• Ocular
• Skin
• Psychological

35
Autosomal recessive inheritance

• Rarely any family history
• 25 recurrence risk
• boys and girls affected in equal numbers
• consanguinity more common
• most inborn errors of metabolism have this mode
  of inheritance

36
Phenylketonuria (PKU)

• Most common amino acid disorder
• Mental retardation is preventable
• Newborn screening
• Increased urine phenylalanine due to decreased
  enzymatic activity of phenylalanine hydroxylase
• Best outcome if diet is maintained for life
• Women with PKU have significantly increased risk
  of delivering malformed infants
• Excellent dietary management necessary to
  reduce this risk.

37
Environmental/Teratogenic Causes of Mental
Retardation

• Fetal alcohol syndrome
• Spectrum of growth deficiency, physical features
  and cognitive deficits
• Pre- or postnatal growth retardation
• microcephaly
• Facies short palpebral fissures, short upturned
  nose with long philtrum
• Cleft lip
• Learning and behavioral problems, with MR and
  significant problems for those with subnormal IQs
• Wide spectrum of other major birth defects may be
  seen but are much less common

38
Evaluation of Mental Retardation

• History prenatal, perinatal, postnatal
• Pedigree 3 generations
• Physical exam
• Minor anomalies
• Neurological findings
• Behavioral phenotypes

39
Evaluation of Mental Retardation

• Chromosomes important
• Fragile X mental retardation
• Unexplained MR, autism
• Males and females
• Especially with family history of MR
• Cranial imaging
• Helpful diagnostically, especially when
  microcephaly or macrocephaly present
• Metabolic testing
• General (urine organic acids), or focused
• Based upon symptoms