3. Dysmorphology and Pediatric Syndromes

Question 1

Define dysmorphology and dysmorphic individuals

Answer 1

“Dys” = Disordered or abnormal; “Morph” = shape

Dysmorphology - study of human congenital defects and abnormalities of body structure that originate before birth.

“Dysmorphic” - individuals whose physical features are not usually found in other individuals with the same age or ethnic background.

Question 2

burden of birth defects among the pediatric population

Answer 2

Birth defects - leading cause of death in the first year of life. They are evident in 2%–3% of newborn infants and in up to 7% of adults.
• 30% of admissions to pediatric hospitals.
• Many are detected by prenatal ultrasound.

An important task for the clinician presented with an infant with a birth defect is to determine whether the problem is isolated or part of a larger embryopathy (or syndrome).

Question 3

Discuss the various mechanisms of dysmorphology and give examples

Answer 3

Developmental Biology - neural tube defect

Cellular Interactions - SCID

Environmental factors - Phocomelia

Mechanical Factors - Pulmonary hypoplasia

Question 4

differentiate between major and minor anomalies and give examples

Answer 4

Major Abnormalities

Severe, impair normal body function and require surgery for management (eg.,cleft palate, congenital heart disease, etc).
They may be isolated or multiple affecting different body systems.

Minor Abnormalities

Primarily of cosmetic significance (e.g. small ear, sixth finger, clinodactyly, etc).

They occur with variable frequencies in the normal population.

Question 5

malformation vs malformation sequence vs malformation syndrome

Answer 5

Malformation: a morphologic abnormality due to an abnormal developmental process (morphogenesis) eg., cleft lip. - structure of organ

Malformation sequence: a pattern of multiple defects resulting from a single primary malformation. Eg., meningomyelocele and hydrocephalus from a lumbar neural tube defect

Malformation syndrome: cluster of malformations that occurs in a recognizable pattern with a known genetic cause. (“syndrome” - “running together”).
Bloom syndrome, Down syndrome, imprinting disorders

Question 6

deformation vs disruption vs dysplasia

Answer 6

Deformation: distortion by a physical force of an otherwise normal structure - club foot

Disruption: destruction of a tissue that was previously normal - amniotic band syndrome - cord wraps around organ and restricts blood supply organ does not grow .

Dysplasia: abnormal cellular organization within a tissue resulting in structural changes—for example, within cartilage and bone in skeletal dysplasias. Achondoplasia - abnormal CT

Question 7

different causes of malformation syndromes with examples

Answer 7

Single gene disorders (e.g. Bloom syndrome)

Chromosomal disorders (e.g. Down syndrome)

Microdeletion syndromes (e.g. Prader-Willi syndrome)

Polygenic disorders (e.g. club foot)

Environmental causes (Teratogenesis) (e.g. Rubella, congenital viral infection, infant of diabetic mother)

Question 8

clinical features of drug abuse and fetal alcohol syndrome

Answer 8

30-40% of offspring of mothers whose daily alcohol intake >3oz - most harmful in weeks 3-8.

Features: short stature, poor head growth, developmental delay and midface hypoplasia, complex pattern of behavioral and learning problems.

Mid face abnormalities, no indentation in upper lip

Cardiac, nervous system, GU anomalies are commonly seen.

More related to the timing of exposure during the fetal development and do not necessary correlate with the neurological outcome.

Maternal abuse of psychoactive substances - associated with increased risks for miscarriage, preterm delivery, growth retardation, and increased risk for injury to the developing CNS - thromboembolic events .

Methamphetamine and crack cocaine may cause vascular accidents.

Question 9

clinical features of maternal anticonvulsant effects

Answer 9

Affects ~10% of children born to women treated with anticonvulsants.

Characterized by small head circumference, anteverted nares, cleft lip and palate (occasionally), and distal digital hypoplasia.

Risks for spina bifida are increased, especially in pregnancies exposed to valproic acid.

If on older antiepileptic switch to newer one

Question 10

clinical features of retinoic acid embryopathy

Answer 10

Vitamin A and its analogs have considerable teratogenic potential.

~1/3rd of pregnancies exposed in the first trimester to the synthetic retinoid isotretinoin, commonly prescribed to treat acne.

Features: CNS malformation, ear anomalies; congenital heart disease (great vessel anomalies); and tracheoesophageal fistula.

Vitamin A intake is limited to 10,000 IU/day of retinoic acid

Retinol is OK! Retinoic acid is NOT

Question 11

risks in assisted reproduction and its effect on genetic imprinting

Answer 11

ART - the actual number of viable embryos is limited and questions about the risks of adverse effects continue to be raised.

Increased rates of twinning, increased rates of birth defects - issues with imprinting disorders.

Abnormal genetic imprinting - INC Beckwith-Wiedemann and Angelman syndromes among offspring of in vitro pregnancies

Angelman syndrome: imprinting disorder (severe intellectual disability, seizures, like water, wide spaced teeth, always happy)

Question 12

different tests used for maternal blood analysis

Answer 12

A (pregnancy-associated plasma protein A) and the free β-subunit of human chorionic gonadotropin (hCG), maternal α-fetoprotein (AFP), hCG, unconjugated estradiol, and inhibin (“quad screen”) - estimate risks for trisomies 21 and 18.

FIRST trimester (12wks) screen for trisomy 18 and 21- look at hormone levels of:
PAPA and free B-subunit of human chrorionic gonadotropin (hCG)

SECOND trimester (12-26) “quad screen” - looks at hormone levels of maternal α-fetoprotein (AFP), hCG, unconjugated estradiol, and inhibin

PAPA and inhibin increase in trisomy
HCG, unconjugated estradiol, AFP decrease in trisomy

NextGen sequencing - specific chromosome imbalances.

Screening tests - need to be confirmed by another method.

Question 13

different tests used for fetal sample analysis

Answer 13

Chorionic villus sampling: At 11–12 wks gestation.

Amniocentesis: early 2nd trimester (15–16 wks gestation).

Fetal blood and tissue: late gestation through ultrasound-guided percutaneous umbilical blood sampling (PUBS).

Preimplantation genetic diagnosis: genetic diagnoses in pre-implantation human embryos.

Question 14

different tests used for fetal imaging

Answer 14

Fetal Ultrasonography - Pregnancies at increased risk for CNS anomalies, skeletal dysplasias, and structural defects of the heart and kidneys - common way to see birth defect.

Fetal MRI - suspected fetal CNS abnormalities as well as in other fetal anomalies - if need more information.

Question 15

different components in the evaluation of a dysmorphic infant

Answer 15

History and physical examinations provide most of the clues to diagnosis

Pregnancy History
Review of gestational age, intrauterine drug exposure, prenatal complications, and prenatal testing is important.

Family histories are preferred in pedigree formation.

Environmental histories should include descriptions of parental habits and work settings.

Physical Examination
Meticulous physical examination is crucial for accurate diagnosis in dysmorphic infants and children.

Special attention should be paid to the neonate’s physical measurements. Photographs are helpful and should include a consistent method of measurement for reference.

Question 16

Differentiate between the utility of a skeletal survey, magnetic resonance imaging, computed tomography, ultrasonography and cytogenetic analysis

Answer 16

Skeletal survey (x-ray of all bones)- evaluation of patients with suspected skeletal dysplasia.

Magnetic resonance imaging (MRI) - deep tissue evaluation

Computed tomography (CT) - is useful for bony structure assessment.

Ultrasonography - case-dependent utility for noninvasive imaging.

Cytogenetic analysis provides specific diagnoses in approximately 5% of dysmorphic infants who survive the neonatal period. Chromosomal abnormalities are recognized in 10%–15% of infants who die.

As a rule, a normal karyotype does not rule out the presence of significant genetic disease.

Diagnostic yield of Exome Sequencing - about 25% in pediatrics and 17% in adults.

Question 17

Fragile X

Answer 17

expanison of CGG repeats (>200) - turns off FMR1 gene - nervous system dysfunction

X-linked Dom

characteristics become more apparent with age

most common inherited cause of intellectual disability (1/2500 males, 1,5000 females)
MOST common identified cause of ASD

clinical fts: 
intellectual diability (mild-moderate)
long and narrow face
large face, prominent jaw and forehead 
flexible fingers (double jointed)
flat feet 
in males - enlarges testicles (macroorchidism) after puberty
ASD, ADHD

Question 18

Marfan

Answer 18

FBN1 mutation - fibrillin mutations of this gene alter structure of CT

Fibrillin - forms ECM and CT, will have issue with CT

Auto Dom

characterized by ocular, skeletal and CV defects (Abe Lincoln)

clinical fts: ocular, skeletal and CV defects

ocular- myopia and displaced lens (ectopia lentis)

skeletal - dolichostenomelia (long limbs), pectus excavatum, pectus carinatum, scolosis and arachnodactyly and joint hypermobility

CV (fatal) - mitral valave prolapse, aortic dilatation (90%) - cardiomyopathy - CHF