Common Malformations

Question 1

What is the definition of a minor anomaly?

Answer 1

A developmental difference that may be important for diagnosis, but has no
physical impact
* Single palmar crease, clinodactyly

Question 2

What is the definition of a major anomaly?

Answer 2

A congenital anomaly that causes a problem requiring medical or surgical
intervention
* Heart defect, cleft lip or palate, Hirschsprung

Question 3

What is a deformation?

Answer 3

An external factor produces abnormal shape due to pressure and/or restriction of
growth and movement
* Club foot: Talipes equinovarus
* Can be due to fetal constraint

Question 4

What kind of anomaly is talipes equinovarus “club foot”?

Answer 4

Deformation

Question 5

What kind of anomaly is plagiocephaly?

Answer 5

Deformation

Question 6

What is a disruption?

Answer 6

A disruption implies an interruption to the developmental process
* Interpreted in different ways
* Vascular interruptions
* Maternal exposures
* Alcohol
* Medications
* Similar to deformation, the developmental process would have been normal

Question 7

What kind of process is phocomelia from thalidomide?

Answer 7

Disruption

Question 8

What kind of process is Klippel Feil (non-separation of cervical vertebrae? What is thought to cause it?

Answer 8

Disruption.
Majority sporadic. Hypothesized to be “Subclavian Artery Supply Disruption Sequence”

Question 9

What kind of process is involved with Moebius?

Answer 9

Disruption
Bilateral facial and abducens nerve palsies. “Cross-eyed”

Question 10

What kind of process is involved with Poland syndrome (absence of pectoralis, breast hypoplasia, missing ribs)?

Answer 10

Disruption

Question 11

What kind of process is involved with Hemifacial microsomia (Goldenhaar syndrome)?

Answer 11

Disruption

Question 12

What is a malformation?

Answer 12

A malformation is birth anomaly in which the developmental instructions were incorrect

Question 13

What is dysplasia?

Answer 13

Abnormal cell type, differentiation, or growth
* Often used with cancer

Question 14

What is hyperplasia?

Answer 14

Excessive growth

Question 15

What is hypoplasia?

Answer 15

Inadequate growth

Question 16

What is atrophy?

Answer 16

A normal structure shrinks over time

Question 17

What kind of growth process is seen with Beckwith Wiedemann Syndrome?

Answer 17

Macroglossia and hemihypeplasia

Question 18

What is a sequence?

Answer 18

• “One thing leads to another”
• Can involve multiple mechanisms, including malformation,
  disruption, and deformation

Question 19

What are the features of PIERRE ROBIN SEQUENCE?

Answer 19

• Small mandible
• Tongue displaced posteriorly
• Tongue blocks the fusion of the
  palate in the midline
• Severe cases: Tongue impairs
  formation of larynx

Question 20

What are the two most common disorders with Pierre Robin sequence?

Answer 20

Stickler Syndrome (25% of PRS)
Deletion 22 syndrome

Question 21

What is an association?

Answer 21

A collection of anomalies that are
recognized to be co-occurring at
higher-than-expected statistical
chance

e.g. VACTERL (no genetic cause)

Question 22

What does VACTERL stand for?

Answer 22

• V: Vertebral
• A: Anorectal malformation
• C: Cardiac
• T: Tracheo-esophageal atresia/fistula
• E: Ear anomaly
• R: Renal anomaly
• L: Limb (radial ray / thumb side)

Question 23

What is MURCS association?

Answer 23

• Mullerian
• Ureteral
• Renal
• Cervicothoracic
• Somite abnormalities
• Uterine anomalies, fallopian tube abnormalities
• Vas deferens anomalies in males
• Cervical vertebral fusions—Klippel Feil. Also can have Sprengel
• Hearing loss

Question 24

What is the result of failure of fusion of maxillary prominences to the medial nasal prominence?

Answer 24

Cleft lip/cleft palate

Question 25

What is gastroschisis?

Answer 25

• Protrusion of intestines through the abdominal wall
• Believed to be a disruption event
• Interruption of the omphalomesenteric artery (PMID: 6450826)

Question 26

What is gastroschisis associated with?

Answer 26

Trisomies (~1%)
Young maternal age, smoking, alcohol, vasoactive medications

Question 27

What is an omphalocele?

Answer 27

Protrusion of intestines, but with covered sac onto which umbilical cord attaches.
* Developmental anomaly—intestines are not properly pulled back into the abdomen
* Seen with chromosomal disorders and Beckwith-Wiedemann syndrome (imprinting)
* Large omphaloceles involving liver, etc, point to trisomy 18 and others.

Question 28

What is craniosynostosis?

Answer 28

Premature fusion of one or more cranial sutures.

Typically present at birth

Diagnosed by x-ray or CT scan

Question 29

What other systems do you look at with craniosynostosis syndrome?

Answer 29

Look at the hands and feet

Question 30

What genes are responsible for the most common causes of craniosynostosis?

Answer 30

FGFR1 (Pfeiffer)
FGFR2 (Apert syndrome)
FGFR3 (Muenke syndrome, Pfeiffer)
Gain of function

TWIST: Saethre Chotzen (LoF, deletion)

Question 31

What are the genes responsible for Pfeiffer syndrome and what is the phenotype?

Answer 31

FGFR1, FGFR2 (AD)

Type 2: Cloverleaf skull

Large thumb
Large toes, toe fusion
Can have ID

Question 32

What is the gene responsible for Apert syndrome and what is the phenotype?

Answer 32

• FGFR2 (AD)
• Craniosynostosis (Bilateral coronal)
• “Mitten hand” malformation (Complex syndactyly)

Associated anomalies:
* Hearing loss
* Intellectual disability
* CNS malformations
* Choanal stenosis (narrow nasal passage)
* Tracheal anomalies – “tracheal sleeve”

Question 33

What is the gene responsible for Crouzon syndrome and what is the phenotype?

Answer 33

FGFR2 (AD)

• Normal hands
• Midface hypoplasia leads to shallow orbit
• Proptosis
• Risk for blindness
• Narrow, sometimes beaked, nose
• Usually normal development
• Hearing loss

Question 34

What is the gene responsible for SAETHRE-CHOETZEN syndrome and what is the phenotype?

Answer 34

TWIST, FGFR2 (AD)

• Craniosynostosis
• Facial asymmetry
• Ptosis
• Small, rotated ears
• Brachydactyly, mild hand and foot anomalies