consultation with the specialist
The Pierre Robin Sequence:
Additional media illustrating features of
the disease processes discussed are
available in the online version of this
article at www.pedsinreview.org.
A Concise Review for the
Practicing Pediatrician
Matthew R. G. Taylor, MD*
Introduction
The Pierre Robin sequence (PRS)
describes a clinical triad of cleft pal-
ate, micrognathia, and glossoptosis.
The condition is considerably more
complicated than isolated cleft pal-
ate. Substantial respiratory and feed-
ing problems may arise in affected
individuals. A timely diagnosis made
by an experienced pediatrician is im-
portant in attenuating these feared
consequences. Several causes of PRS
have been elucidated, some of which
are heritable and have implications
for other siblings and future children.
Case Report
A male infant was born to a G2P1 3
2 healthy mother at 36.5 weeks of
gestation. The pregnancy was com-
plicated by maternal hypertension.
Normal fetal movements and normal
amniotic fluid were reported. The
birthweight was normal, and initial
Apgar scores were 7 and 9 at 1 and
5 minutes, respectively. The infant
was noted to have a “small” jaw and
within 1 hour of birth was experienc-
ing significant respiratory difficulties
and cyanosis. High-flow oxygen and
placement in a prone position im-
proved his condition only tran-
siently, and he was transferred to a
tertiary care hospital. A cleft palate
was noted, and shortly after arrival,
endotracheal intubation was per-
formed due to his deteriorating re-
spiratory status. Severe PRS was sus-
pected, and a tracheostomy was
performed on day 10 of life.
*Division of Genetic Services, University of Colorado
Health Sciences Center, Denver, CO.
The genetic evaluation noted an
unremarkable family history. No rel-
atives suffered from PRS, cleft palate,
or features of an obvious related ge-
netic condition. Physical examina-
tion revealed a weight of 3,050 g
(50th percentile), head circumfer-
ence of 32.5 cm (40th to 50th per-
centile), and length of 52 cm (90th
percentile). His facial features were
striking and included severe micro-
gnathia, a palatal cleft, and obvious
midface hypoplasia. His eyes and ears
appeared normal. No heart murmur
was noted, and findings on abdomi-
nal, genital, and extremity examina-
tions were normal. The geneticist
suspected Stickler syndrome based
on the PRS and the facial features.
The diagnosis was confirmed when
an ophthalmologic examination per-
formed at 6 months of age revealed
ocular features diagnostic for Stickler
syndrome.
The child’s medical condition was
stabilized, and he was discharged re-
quiring continued oxygen therapy
via his tracheostomy and a feeding
tube. He was re-evaluated by the ge-
neticist at the age of 9 months. At
that time, his weight and growth
were improving steadily, and plans
were discussed to remove his trache-
ostomy tube. Oral feeding remained
limited, and there were no im-
mediate plans to discontinue the
feeding tube. His facial features re-
mained abnormal, although the
retrognathia was less pronounced
than at birth (Figure). Motor and
cognitive development were appro-
priate for age. He successfully un-
derwent palatal correction surgery
at age 10 months.
Pediatrics in Review Vol.22 No.4 April 2000 125
consultation with the specialist
Figure. Boy who has PRS at 9 months of age. Note retrognathia, which had improved
since birth.
Historical and Clinical
Importance
In 1923, Pierre Robin, a famous
French stomatologist, characterized
and described a group of patients
who suffered from cleft palate, mi-
crognathia, and glossoptosis (the ob-
served tendency of the tongue to
move posteriorly and obstruct the
oropharynx). Although similar fea-
tures had been described previously,
his meticulous documentation of the
triad of findings led to the recogni-
tion of the sequence that bears his
name today. Often considered in the
context of a cleft palate, PRS is esti-
mated to affect approximately 1 in
8,500 births. Palatal clefts are not
uncommon in pediatric patients (in-
cidence of approximately 1 in 1,000
live births), but the significant respi-
ratory problems associated with PRS
underscore the importance of distin-
guishing this sequence from simple
cleft palates. Continuing advances in
prenatal ultrasonography permit
physicians to identify findings sug-
gestive of the PRS and help antici-
126 Pediatrics in Review Vol.22 No.4 April 2000
pate the perinatal management of
affected fetuses.
Definition
Although the expressed phenotype
of PRS is variable, three clinical find-
ings generally are cited as defining
components of the sequence: 1) cleft
palate, 2) micrognathia, and 3) glos-
soptosis (Table 1). Some authors do
not require the presence of a cleft
palate to make a diagnosis, relying
instead on the presence of marked
micrognathia (or retrognathia) and
glossoptosis. Other, more restrictive
Definition of
Table 1.
Pierre Robin
Sequence
● Cleft palate (full or submucous)
● Micrognathia/Retrognathia
● Glossoptosis
● Respiratory compromise*
*Suggested by some authors as necessary for
diagnosis.
investigators have suggested that ev-
idence of respiratory compromise is
needed to meet the sequence defini-
tion. This last definition, however,
may fall short in identifying all af-
fected patients at risk for respiratory
difficulties. For example, those who
have less severe PRS may not experi-
ence respiratory problems until they
require general anesthesia and endo-
tracheal intubation. Children who
have PRS probably should not re-
ceive anesthesia unless appropriate
airway management measures are in
place. It is the clinical recognition
that severe micrognathia predicts re-
spiratory compromise that often be-
comes most immediately relevant.
The abnormal anatomy associated
with retrognathia and glossoptosis
can make airway management a con-
siderable challenge. Probably all pa-
tients who have cleft palate or a his-
tory of a repaired cleft palate should
be examined for findings of PRS.
Because the criteria for defining
PRS are variable, reported preva-
lences also vary. Estimates range
from 1 in 2,000 to 1 in 30,000 live
births. As noted previously, one
commonly cited estimate suggests a
prevalence of 1 in 8,500. The lack of
consensus for a standard definition
makes approximation of mortality
figures troublesome; historically, es-
timates of a 25% mortality have been
suggested.
Sequence Versus Syndrome
The available literature describes
PRS as a sequence and a syndrome.
The two terms are not equivalent and
appreciating the distinction between
them is important when considering
the condition and understanding its
pathogenesis. PRS anomalies per-
haps are considered best as represent-
ing a sequence rather than a syn-
drome.
Syndromes refer to collections of
abnormalities that often vary in de-

gree and pattern of expression, but
ultimately are believed to result from
a single distinct pathologic event/
process. Thus, a syndrome may be
thought of as resulting from a partic-
ular disease. Down syndrome pro-
vides a simple illustration of this
concept. Hypotonia, upslanting pal-
pebral fissures, epicanthic folds, sim-
ian creases, cardiac defects, increased
distance between the first and second
toes, and mental retardation are fea-
tures that commonly are associated
with Down syndrome. These clinical
findings display a certain degree of
variability (eg, one patient may suffer
from more or less mental retardation
than another patient). In all cases of
true Down syndrome, the etiology
may be traced to a single pathology
of some form of trisomy 21. Even
though a particular syndrome may
demonstrate variability in phenotype
among affected individuals, a single
common pathologic event or process
is responsible for the syndrome. In
short, a syndrome describes a com-
mon pathologic process leading to a
recognizable phenotype.
Similar to syndromes, sequences
are comprised of a constellation of
anomalies that often vary in the de-
gree of expression, and the group or
pattern of anomalies is believed to
result from prior developmental
anomalies or mechanical processes.
In a sequence, however, these prior
events are not specific to any particu-
lar disease or diagnosis. Instead, a
number of different disease processes
can cause the incipient event and ul-
timately lead to the findings of a spe-
cific sequence. In contrast to a syn-
drome, a sequence describes a variety
of pathologic processes employing
different mechanisms to converge on
a similar phenotype. Instead of de-
scribing an exact diagnosis, recog-
nition of a sequence prompts the
examiner to consider a differential
diagnosis of disease processes associ-
Table 2. Causes of Pierre Robin Sequence
Category
Deformational
Monogenetic
Chromosomal
Teratogenic
Disruption
Unknown cause
Adapted from: Gorlin R, Cohen M, Levin S. Syndromes of the Head and Neck. 3rd ed. Oxford
England: Oxford University Press; 1990:700 –704.
ated with that particular sequence. In
the case of PRS, many diseases or
processes can lead to a problem with
mandibular development. Although
these many insults may appear dis-
similar and are not explained by a
single disease, the effects on the de-
veloping fetus lead to similar recog-
nizable clinical findings.
Etiology
As suggested, the PRS may result
from a variety of prenatal insults that
lead to abnormal palatal and mandib-
ular architecture (Table 2). Being
sensitive to the pathogenic processes
that lead to PRS allows the clinician
to use information obtained from a
medical history and physical exami-
nation of the patient to develop a
more specific diagnostic approach.
Because PRS is not a unique disease,
this approach assists the clinician in
consultation with the specialist
Condition
● Oligohydramnios
● Uterine structural anomalies
● Amniotic band syndrome
● Stickler syndrome (common cause)
● Beckwith-Wiedermann syndrome
● Camptomelic syndrome
● Cerebrocostomandibular syndrome
● Congenital myotonic dystrophy
● Mandibulofacial dysostosis
● Miller-Dieker syndrome
● Otopalatodigital syndrome II
● Robin-oligodactyly syndrome
● deletion (22q) syndrome (common cause)
● deletion (4q) syndrome
● deletion (6q) syndrome
● duplication (11q) syndrome
● Fetal alcohol syndrome
● Fetal hydantoin syndrome
● Fetal trimethadione syndrome
● Amniotic band sequence
● CHARGE association
● Femoral dysgenesis
● Moebius sequence
● Robin/amelia association
determining what process or disease
led to the PRS in a specific patient.
Findings from a careful history and
detailed physical examination
suggest the probable cause of the
sequence in most patients.
One of the initial characteriza-
tions is a distinction between defor-
mational PRS and malformational
PRS. The deformational causes of
PRS generally are considered to be
isolated conditions that are not asso-
ciated with a syndrome diagnosis; ap-
proximately 40% of PRS cases appear
to be isolated. Deformational pro-
cesses are physical forces that are en-
countered in the setting of oligo-
hydramnios or abnormal uterine
anatomy. Pressures mechanically in-
hibit normal mandibular develop-
ment. Lack of adequate amniotic
fluid leads to compression of the chin
on the sternum and subsequent mi-
Pediatrics in Review Vol.22 No.4 April 2000 127
consultation with the specialist
crognathia. Because the tongue re-
mains between the developing pala-
tal shelves, the palate fails to close
properly. Structural uterine abnor-
malities, such as submucous fibroids,
can compress the developing mandi-
ble. Amniotic bands also are believed
occasionally to restrain mandibular
growth and lead to the PRS. Once
the infant is free from the constraints
of the womb, mandibular catch-up
growth is typical. The prognosis for
patients who have isolated PRS is
good. These diagnoses usually can be
made based on a careful history and a
physical examination that is sensitive
to finding evidence of intrauterine
constraint.
The list of conditions that cause
malformational PRS is considerably
more impressive, and the prognosis
for some is less favorable. Many of
the conditions may be categorized
based on etiology; some of the impli-
cated syndromes are listed in Table 1.
Many of the syndromes have a clear
genetic basis, and the presence of
genetic disease contributing to PRS
is indicated by a suggestive family
history or by dysmorphic features or
anomalies on physical examination.
Nonspecific findings should be inves-
tigated with high-resolution chro-
mosomal analysis. When specific syn-
dromes are likely, attention may be
focused on whether a particular ge-
netic test (eg, fluorescent in situ hy-
bridization or mutation analysis) is
available. Because as many as 60% of
PRS patients have an associated syn-
drome or condition contributing to
the sequence, it is reasonable to have
each affected patient evaluated by a
physician who specializes in genetic
or malformation syndromes.
Of the monogenetic syndromes,
Stickler syndrome deserves mention;
previous authors have suggested that
this entity be considered initially
when PRS is encountered. In fact,
Stickler syndrome has been esti-
128 Pediatrics in Review Vol.22 No.4 April 2000
mated to account for 15% to 30% of
cases of PRS in some series. A disor-
der of type II collagen (sometimes
type XI collagen), Stickler syndrome
causes physical abnormalities because
of the production of abnormal con-
nective tissue. This multisystem
illness leads to ocular problems
(a characteristic vitreous anomaly
and myopia), joint hypermobility,
sensorineural hearing loss, and mid-
line clefting. In some cases, the cleft
palate is in the context of PRS. Pre-
sumably the dysfunctional collagen is
the foundation for abnormal man-
dibular development. In light of this
common association, it is reasonable
to examine all infants who have PRS
for additional stigmata of Stickler
syndrome. Opthalmologic examina-
tion, searching for severe myopia, of-
ten can diagnose Stickler syndrome
at an early age, even in infants.
Another condition that merits
consideration is the velocardiofacial
syndrome (VCFS). First described by
Shprintzen et al in 1981, it is a com-
mon cause of cleft palate; some data
suggest that it may be the most com-
mon midline clefting syndrome. The
original investigators estimated that
VCFS accounts for 8% of all midline
palatal clefts. The more common fea-
tures of this dysmorphic syndrome
include: cleft palate, a typical facies,
cardiac anomalies, immune dysfunc-
tion, and learning disabilities. The
disorder is associated with a deletion
on the long arm of chromosome 22
(22q deletion) and may be tested for
readily in the laboratory. The PRS
frequently is found in affected
patients.
Because the test can be performed
easily and the presence of a positive
test predicts possible cardiac and
mental anomalies, the clinician needs
to consider VCFS in the differential
diagnosis of PRS. A family history
that reveals other family members
who have cleft palate, speech delays,
cardiac defects, immune dysfunction,
learning difficulties, or visual prob-
lems strengthens this diagnostic pos-
sibility.
An evaluation for other possible
genetic causes of PRS involves ob-
taining a careful family history and
physical examination. Not every fam-
ily history will be revealing because a
significant percentage of genetic dis-
eases may represent new mutations.
In challenging cases, referral to a ge-
netic specialist is appropriate. The
geneticist can help determine if PRS
is isolated or a manifestation of a
specific syndrome.
Several teratogens have been im-
plicated as causes of PRS. For exam-
ple, prolonged maternal exposure to
alcohol has been associated with
PRS. The pathogenesis of the se-
quence under these conditions is not
known, but decreased in utero move-
ment by the fetus may contribute to
mandibular undergrowth. Hydan-
toin exposure has been reported as a
causative factor, although the inci-
dence of the association is not
known.
A final classification is neuromus-
cular disease that leads to fetal hypo-
tonia or myopathic features. Normal
mandibular muscle function in utero
is believed to be necessary for proper
mandibular development. This hy-
pothesis suggests that normal man-
dibular “exercise” in utero is critical
to extend the jaw and prevent micro-
gnathia. Identifying neuromuscular
problems in a patient or eliciting a
prenatal history of decreased fetal
movement or oligohydramnios
(from decreased swallowing) sug-
gests this category of possibilities.
Clinical Presentation
The overall presentation of PRS is
variable, especially within the con-
text of the broader definition of the
syndrome. The classic and severe pre-
sentation includes marked microgna-

thia, cleft palate, and marked respira-
tory problems. Diagnosing less
affected children requires astuteness
on the part of the physician. Typi-
cally, the inspiratory portion of the
respiratory cycle is more compro-
mised. Periodic cyanotic spells, la-
bored inspiratory breathing, or sleep
apnea may be observed. These respi-
ratory difficulties are enhanced in the
supine position. The mandibular an-
atomic changes result in feeding dif-
ficulties, which may be complicated
further by the presence of a cleft pal-
ate. Many patients who have PRS
require gavage feeding for a period of
time. Hearing infections and hearing
loss, presumably from malpositioned
narrow eustachian tubes, also are fre-
quent complications.
Multiple other findings can be
present within the “syndrome” di-
agnoses. Because PRS frequently is
associated with Stickler syndrome,
ocular anomalies are common. Simi-
larly, cardiac defects, which are com-
mon to VCFS and other genetic dis-
orders, often are present. Overall
growth retardation also has been re-
ported. A portion of this problem
may be related directly to the abnor-
mal mandibular anatomy; in other
cases, additional factors (eg, chromo-
somal anomalies) may contribute to a
pattern of poor growth. Some asso-
ciation with limb anomalies has been
described in the literature, with syn-
dactly and polydactly reported most
frequently.
Approach to the Patient Who
Has PRS
A reasonable approach to newly de-
tected PRS is two-tiered. Of prime
clinical importance is proper antici-
pation and treatment of any respira-
tory compromise that arises and at-
tention to nutritional needs. The
anatomic changes in the upper air-
way often lead to severe respiratory
insufficiency, and hypoxic injury is a
very real threat. Compounding this
problem is the associated difficulty
that typically is encountered during
endotracheal intubation. Unsus-
pected PRS that presents at birth can
quickly become disastrous if the
medical staff cannot secure an unob-
structed airway. In cases with some
forewarning, engaging the expertise
of a physician experienced in the
management of such airways can be
lifesaving. The otolaryngology litera-
ture is comprehensive in its discus-
sion of the approach to PRS airway
management.
The degree of clinical problems
evident at the time of diagnosis pro-
vides useful prognostic information.
Not surprisingly, initially severely af-
fected infants do not fare as well as
mildly affected ones. Caouette-
Laberge et al classified 125 patients
who had PRS into three clinical
groups: adequate respiration in
prone position and bottle-feeding
(group 1); adequate respiration in
prone position but feeding difficul-
ties requiring gavage (group 2); and
children who had respiratory distress
and endotracheal intubation and ga-
vage (group 3). The mortality rates
were 1.8%, 10%, and 41%, respec-
tively, in the three groups. The pres-
ence of prematurity or additional
malformations were further negative
predictive factors, but the assigned
group carried the heaviest prognostic
weight. The authors noted that ad-
vances in understanding and man-
agement of PRS may improve the
prognosis.
Therapeutic Interventions
As knowledge and understanding
about PRS has expanded, so has the
development of potential therapeutic
maneuvers to improve the health of
affected patients. Education of family
members and health care profession-
als is important. One of the simplest
interventions is prone positioning of
consultation with the specialist
infants, which is believed to help pre-
vent the tongue and mandible from
obstructing the airway and leads to
generally improved oxygen satura-
tion. Prone position infant car safety
seats have been developed and evalu-
ated for the safety of those who have
PRS. Although a large randomized
trial of such seats has not been per-
formed (and is not likely forthcom-
ing), at least one study has docu-
mented the safety of these seats in a
small population
A variety of more intensive ap-
proaches has been tried for patients
who have severe PRS. Laryngeal
mask airways used transiently in the
setting of respiratory failure have
shown some efficacy. Less invasive
nasopharyngeal airways used both
short term and long term (greater
than 6 wk) have improved parame-
ters such as number of cyanotic epi-
sodes, clinical heart failure, and arte-
rial blood gases. Promising weight
gain with nasopharyngeal airways
also has been suggested. Overall,
multidisciplinary care may hold the
most promise. One study involved
developmental, surgical, pulmonary,
genetic, and social work specialists
and followed the course of 21 PRS
patients. Excepting one patient who
died before being evaluated by the
multidisciplinary team, the group did
well overall.
Feeding difficulties must be ad-
dressed in the management of these
patients. Occupational therapy di-
rected toward management of the
palatal abnormality should be insti-
tuted early. Gastroesophageal reflux
may complicate the PRS, and phar-
macologic therapy directed at this
problem may improve oral feeding.
Palatal clefts cannot always be re-
paired at the time of diagnosis, and
plans for ensuring adequate nutrition
in preparation for future palatal sur-
gery should be invoked. Feeding
tubes are common in severely af-
Pediatrics in Review Vol.22 No.4 April 2000 129
consultation with the specialist
fected PRS patients. In the case of
isolated PRS that involves mandibu-
lar “catch-up” growth, such prob-
lems may not be permanent. Infants
should be evaluated early for palate
repair surgery. The exact timing and
type of surgery for a particular patient
requires the assistance of a palatal
specialist and is beyond the scope of
this review.
Prognostic Factors and
Family Concerns
Patients and their families under-
standably are interested in prognos-
tic information about PRS. Ques-
tions about the possibility of other
family members suffering from PRS
are prominent in cases where genetic
illness is likely. Unfortunately, few
comprehensive guidelines are avail-
able for determining the prognosis.
Historical data clearly show that the
degree of respiratory compromise is a
powerful predictor of both morbidity
and mortality. Those who have iso-
lated PRS are believed to have a bet-
ter long-term prognosis if initial re-
spiratory and feeding problems can
be overcome. Those who have medical
conditions in addition to the mandib-
ular anomalies may have a worse prog-
nosis. For example, a patient who has
Shprintzen syndrome may have a rela-
tively mild PRS, but exhibit a life-
threatening cardiac defect.
130 Pediatrics in Review Vol.22 No.4 April 2000
Finally, it may not be entirely rea-
sonable to rely on figures presented
in historical data for prognosis. Ad-
vances in the management of PRS
may be affecting the survival of pa-
tients who have PRS, as some au-
thors have suggested. The data from
management by multidisciplinary
teams are encouraging.
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