Association Syndromes and Sequences

Question 1

What anomalies are included in the CHARGE

association?

Answer 1

C Coloboma
H Heart defect
A Atresia, choanal
R Retarded growth and development
G Genital hypoplasia
E Ear anomalies/hearing loss

Question 2

What are poor prognostic factors in patients with

CHARGE association?

Answer 2

Midline malformations, esophageal atresia, and bilateral

choanal atresia

Question 3

What head and neck anomalies are related to the

CHARGE association?

Answer 3

Choanal atresia, ear abnormalities and hearing loss, facial

nerve palsy, pharyngoesophageal dysmotility, laryngomala-
cia, vocal-cord paralysis or paresis, obstructive sleep apnea,

tracheoesophageal fistula, and gastroesophageal reflux.
Temporal bone abnormalities, such as hypoplasia of the
semicircular canals and Mondini malformation can also occur.

Question 4

What gene is involved in the CHARGE association?

Answer 4

CHD7 gene (member of the chromodomain helicase DNA
protein family), chromosome 8q12 in 75% of patients with
CHARGE association

Question 5

What is the incidence of choanal atresia in

patients with CHARGE association?

Answer 5

> 65%, > 2/3 bilateral. If unilateral, left > right

Question 6

What does VACTERL association stand for?

Answer 6

V Vertebral defects
A Anal atresia
C Cardiac malformations
TE Tracheoesophageal fistula with esophageal atresia
R Renal dysplasia
L Limb anomalies (most commonly radial anomalies)

Question 7

What percentage of patients with VACTERL

association have a tracheoesophageal fistula?

Answer 7

50 to 80%

Question 8

What are the major clinical characteristics in

patients with velocardiofacial syndrome?

Answer 8

Clefting of the secondary palate, hypernasal speech, pha-
ryngeal hypotonia, structural heart anomalies, dysmorphic

facial appearance, slender hands and fingers, and learning
disabilities

Question 9

What chromosomal anomaly is associated with

velocardiofacial syndrome?

Answer 9

About 80 to 100% have a hemizygous deletion of

chromosome 22q11.

Question 10

What factors lead to velopharyngeal insufficiency

in patients with velocardiofacial syndrome?

Answer 10

Cleft palate (occult submucous cleft, overt submucous cleft
or soft palate cleft), hypotonia of the pharyngeal muscles,
platybasia (an obtuse angulation of the cranial base), and a
small adenoid pad

Question 11

Why do most patients with velocardiofacial
syndrome have chronic otitis media and conductive
hearing loss despite having a small adenoid pad?

Answer 11

Abnormal craniofacial anatomy, cleft palate, and associated

eustachian tube dysfunction

Question 12

What evaluation must be done when performing a
pharyngeal flap on a patient with velocardiofacial
syndrome? Why?

Answer 12

Nasopharyngoscopy (look for pulsations in the posterior or

lateral pharyngeal walls), computed tomography angiog-
raphy (CTA), or magnetic resonance angiography (MRA); 25

to 30% have medial displacement of their internal carotid
arteries.

Question 13

What autosomal dominant syndrome is most
likely in a child with lower-lip pits, cleft lip,
and/or cleft palate?

Answer 13

Van der Woude syndrome

Question 14

Describe lower-lip pits in van der Woude

syndrome.

Answer 14

Usually bilateral paramedian sinuses in the lower lips placed
symmetrically on either side of midline. They can also be
median, paramedian, or unilateral (usually left). A single
median or paramedian lower lip pit is considered an
incomplete expression of the trait.

Question 15

Describe the embryologic formation of lower-lip

pits as seen in van der Woude syndrome.

Answer 15

The lower lip of a 32-day embryo consists of four growth
centers divided by one median and two lateral grooves. In
the 38-day embryo, the lateral grooves disappear unless
there is impeded mandibular growth, which results in the
formation of a lower lip pit.

Question 16

What are the clinical features of Stickler syndrome?

Answer 16

Typical facial characteristics (micrognathia leading to Pierre
Robin sequence), hypermobility, and enlargement of joints
associated with the onset of arthritis in early adulthood,
myopia, retinal detachment, cataracts, and hearing loss

Question 17

What is the genetic mutation in Stickler syndrome?

Answer 17

Mutations in the COL2A1, COL9A1, COL11A1, and COL11A2
genes cause Stickler syndrome. These genes are involved in
the production of type II, type IX, and type XI collagen,
which are components of vitreous, cartilage, and other
connective tissues.

Question 18

What are the different types of Stickler syndrome,

and what are the associated genetic mutations?

Answer 18

● Type 1 (autosomal dominant) are mutations in the
COL2A1 gene and are the most common.
● Type 2 (autosomal dominant) are mutations in the
COL11A1 gene.
● Type 3 (autosomal dominant) are mutations in the
COL11A2 gene. No ocular abnormalities because COL11A2
is not present in the vitreous.
● Type 4 (autosomal recessive) are mutations in COL9A1.

Question 19

What are the clinical findings in Pierre Robin

sequence?

Answer 19

Micrognathia, glossoptosis, and wide U-shaped cleft palate,

leading to upper airway obstruction and feeding difficulties

Question 20

Describe the embryology of Pierre Robin

sequence.

Answer 20

Arrest in mandibular development at 7 to 11 weeks of

gestation (micrognathia) causes the tongue to set abnor-
mally high and posteriorly in the oral cavity (glossoptosis).

This prevents fusion of the palatal shelves at week 11 and
results in a U-shaped cleft palate.

Question 21

What are the most common syndromes associated

with Pierre Robin sequence?

Answer 21

● Stickler syndrome (most common)
● Treacher Collins syndrome
● Velocardiofacial syndrome
● Fetal alcohol syndrome
● Möbius syndrome
● Nager syndrome
● Beckwith-Wiedemann syndrome

Question 22

How often is Pierre Robin sequence associated

with a syndrome?

Answer 22

80% (20% isolated)

Question 23

Discuss the treatment options for upper-airway

obstruction in patients with Pierre Robin sequence.

Answer 23

● 70%: Positioning alone (i.e., prone positioning)
● 20%: Nasopharyngeal airway, mandibular distraction
osteogenesis (gaining popularity), tongue-lip adhesion
(being performed less commonly)
● 10%: Tracheostomy