Pierre Robin Sequence in Denmark: A Retrospective Population-Based

Epidemiological Study
ANDREAS PRINTZLAU, M.D.
MIKAEL ANDERSEN, M.D.
Objective: To give an epidemiological description of the clinical entity given
the name Pierre Robin sequence, defined by retro- and micrognathia, cleft palate, and respiratory distress and describe other malformations and possible
intrauterine impairment.
Methods: Using the inclusion criteria of micrognathia, cleft palate, and neonatal respiratory distress, a retrospective population-based study of all Danish
live births during 1990 through 1999 were carried out. We found 50 children,
25 boys and 25 girls, fulfilling the inclusion criteria, giving an incidence of 1
in 14,000 live births.
Results: Two-thirds (n 5 33) of the children had the classical U-shaped cleft
palate. More than one-third (n 5 19) had one or several other malformations,
and in five patients the triad of Pierre Robin was a minor feature of a complex
syndrome. The most common noncomplex syndrome was the Stickler syndrome found in 6 of the 50 patients. More than one-fourth (n 5 17) had some
kind of intrauterine impairment, with no specific obstetric diagnosis predominant. Consistent with this, the average birth weight was well below normal.
Conclusions: Several authors have stated that the triad of Pierre Robin is
not a nosological entity, in that it has diverse etiology and diverse pathogenesis. We conclude that the triad of Pierre Robin still can be regarded as a
clinical entity, readily defined at birth, experiencing the same neonatal problems in varying degrees and hence the possibility of designing treatment protocols for later scientific evaluation.
KEY WORDS: cleft palate, epidemiology, micrognathia, Pierre Robin, retrognathia, Robin sequence, Stickler syndrome, syndromes, upper airway
obstruction

In the beginning of the 20th century, the French physician

Pierre Robin treated children with glossoptosis and identified a small population of neonates who had a combination of
micrognathia and glossoptosis, resulting in severe respiratory
problems and a high mortality (Robin, 1934). These children
were designated as having the Pierre Robin syndrome.
In the 1950s during the era of syndromology, it was described by several authors that the triad of micrognathia, glossoptosis, and cleft palate was seen in several different syndromes as well as an isolated combination of features. It was
therefore labeled the Pierre Robin anomalad (Smith, 1975),
i.e., a combination of features going together in different
developmental disturbances.

The term Pierre Robin sequence has become popular, claiming that the primary developmental disturbance is the micrognathia leading to a retropositioning of the tongue, obstructing
the fetal closure of the secondary palatal shelves, and eventually causing neonatal respiratory problems by mechanical
obstruction of the oropharynx (Hanson and Smith, 1975; Cohen, 1999).
Some controversy exists in the literature regarding the individual features of the triad of Pierre Robin. Most authors do
not distinguish between retro- and micrognathia, the latter being a true hypoplasia of the mandible and the former a relative
posterior displacement of the mandible secondary to a decreased angle of the base of the skull as seen in many syndromes (Shprintzen, 1992).
Historically, cleft palate has not been regarded pathognomonic of the Pierre Robin population, and even today some
authors regard this feature as optional. At the other end of the
spectrum, some authors regard only children with a typical
long, U-shaped cleft as being truly Pierre Robin (Shprintzen,
1988).
There have been some investigations into the nature of the
respiratory problems, and most children experience a true glos-

Dr. Printzlau and Dr. Andersen are with the Clinic of Plastic Surgery and
Burns, University Hospital of Copenhagen, Copenhagen, Denmark.
Parts of this paper were presented at the 9th International Congress on Cleft
Palate and Related Craniofacial Anomalies, Gothenburg, Sweden, June 2001,
and at the 29th annual meeting of the Society for Ear, Nose, and Throat Advances in Children (SENTAC), San Diego, California, December 2001.
Submitted May 2002; Accepted March 2003.
Address correspondence to: Andreas Printzlau, M.D., Clinic of Plastic Surgery and Burns, University Hospital of Copenhagen, DK2100 Copenhagen ,
Denmark. E-mail aprintzlau@hotmail.com.
47

48

Cleft PalateCraniofacial Journal, January 2004, Vol. 41 No. 1

soptosis. However, some of the children actually have a narrowing of the oropharynx caused by a collapse of the pharyngeal walls or a combination of the collapse and glossoptosis
(Sher, 1992).
The triad of Pierre Robin can be seen as an isolated phenomenon or in combination with other malformations. There
has been some controversy about whether to include children
with other well-known syndromes in the populations of Pierre
Robin. For instance, children with Treacher Collins syndrome
can actually have all three features of the Pierre Robin triad,
and some authors include these but others do not (Cohen,
1989; Shprintzen, 1992).
Intrauterine impairment is frequently reported in Pierre Robin populations. Oligohydramnios has been suggested as the
cause of micrognathia by physical compression of the fetal
mandible, subsequently leading to cleft palate and respiratory
distress. Even generalized intrauterine impairment like fetal
alcohol syndrome can include the Pierre Robin triad (Cohen,
1989).
The majority of detailed descriptions of the Pierre Robin
sequence are based on series from large treatment facilities and
hence not truly epidemiological (Shprintzen, 1992; CaouetteLaberge et al., 1994; Holder-Espinasse et al., 2001). The few
population-based studies are typically drawn from large registries that do not give a detailed insight into the populations
(Bush and Williams, 1983; Kallen et al., 1996; Lary and Paulozzi, 2001).
The purpose of this study was to give an epidemiological
description of the clinical entity given the name Pierre Robin
sequence, defined by retro- and micrognathia, cleft palate, and
respiratory distress and describe other malformations and possible intrauterine impairment.
MATERIAL

AND

METHODS

This epidemiological study is a population-based, retrospective study based on case records. Denmark has a homogeneous
population of 5 million inhabitants. For the last 20 years, the
annual birth rate has been approximately 67,000 births. By
law, all cleft cases in newborns have to be reported to a centralized register at the University Hospital of Copenhagen
(Christensen, 1999). It is therefore possible to make a population-based epidemiological survey of all Pierre Robin cases
if cleft palate is included as a criterion.
In the event of the live birth of a child with a facial cleft,
the midwife or birth clinic must report directly to the cleft
register at the University Hospital of Copenhagen. The child
and family receive a visit from a specially trained cleft nurse
within the first few days after birth. The cleft nurse writes a
report that includes demographic data, ethnicity, obstetrical
data, cleft-related information including malformations such as
Pierre Robin sequence, and information on the childs ability
to thrive. These reports are collected and retained at the University Hospital of Copenhagen and later included in the
childs case record.
All children with cleft palate are treated by a palatoplasty

FIGURE 1 Retro/micrognathia in a child with Pierre Robin sequence.

within the first 24 months of life. In mild cases of Pierre Robin,

the time of palatoplasty is the first consultation by a physician
in the cleft center at the University Hospital of Copenhagen.
At this age, a possible retro/micrognathia is evaluated and
physical measurements of the cleft palate are performed. Severe cases of Pierre Robin are transferred to the cleft center
in the neonatal period, either for observation and treatment in
the pediatric unit or treatment by the plastic surgeons with
labioglossopexy (tongue-lip-adhesion). However, the evaluation of retro/micrognathia and cleft palate was done at the time
of palatoplasty, even in these cases.
Because the register itself is a cleft register, which does not
include detailed descriptions of the children, this particular information is obtained from the case records. The inclusion criterion for this study were live-born children delivered during
1990 through 1999 displaying retro- or micrognathia, cleft palate, and respiratory distress, regardless of any other concomitant malformation or intrauterine impairment.
It was not possible to distinguish between retro- and micrognathia because neonatal cephalometrics were not obtained.
The diagnosis of a small lower jaw was established if two
clinicians stated so in the case record files (Fig. 1). Based on
the statement by the cleft surgeon at the time of the palatoplasty, the cases were graded as mild, moderate, or severe.
Any overt types of cleft palate were included. The length
of the cleft was graded according to Jensen et al. (1988), ranging from grade I (cleft of the soft palate only) to grade IV
(cleft including the entire secondary hard palate) (Table 1).
The cleft surgeon assessed the shape of the cleft and the cleft
width, measured by calipers at the posterior border of the hard
palate, at the time of the palatoplasty.
The cleft nurse evaluated possible respiratory distress in the
neonatal period by observing the child during supine positioning, feeding, and sleep. Respiratory problems were also graded

Printzlau and Andersen, PIERRE ROBIN SEQUENCE IN DENMARK

49

TABLE 1 Grading of Cleft Palate (Jensen, 1988)

Cleft Palate
Grade

Grade 1
Grade 2
Grade 3
Grade 4

Length of Cleft

Soft palate only

Soft and up to one-third of secondary hard palate
Soft and .one-third of secondary hard palate up to subtotal
Total cleft palate

clinically as mild, moderate, or severe. Consistent respiratory

problems during feeding but only intermittently during supine
positioning were graded as mild. Consistent respiratory problems in the supine position and intermittently during sleep
were graded as moderate. Respiratory problems at rest even
during right positioning (prone and with jaw support) were
graded as severe. The degree of the respiratory problem was
obtained primarily from the cleft nurse report but in more severe cases occasionally from the case record file from either
the pediatric or cleft center record file.
All children were examined by an obstetrician in the neonatal period and referred to the department of clinical genetics
only on suspicion of malformations or syndromes other than
Pierre Robin itself. Any reported concomitant malformation
was obtained from the relevant case record file.
Malformation in a single other organ system (e.g., extremities) was regarded as a minor malformation. Other known
syndromes (e.g., Stickler syndrome) were recorded. Malformations in more than one organ system but not diagnosed as
a specific syndrome were registered as a complex malformation. Only a small number of children were examined by chromosome analysis, and these were therefore not included in this
study.
The childs weight and length at birth and any report of
intrauterine impairment were obtained from the obstetrical record file. Preterm was defined as birth before the end of the
37th gestational week. Small for date was defined by a birth
weight less than 10% of the expected (guideline from the Danish Health Authorities), i.e., less than 2800 g.
RESULTS
During 1990 through 1999, 48 children meeting the inclusion criteria were born in Denmark (excluding Greenland and
the Faroe Islands). The overall number of live births in the
period totaled 670,001, yielding a prevalence of 1/14,000 live
births. The actual yearly occurrence ranged from two to seven
children. One additional child was born on the Faroe Islands
and another born in Greenland. One child was born of immigrant parents. The boy-to-girl ratio was 1:1, with 25 in each
group.
Eight children (16%) had mild retro/micrognathia, 19 children (38%) moderate, and 23 children (46%) had severe retro/
micrognathia. Fifteen (65%) of the 23 children with severe
retro/micrognathia were girls, and hence the respiratory problems were on average more pronounced among girls.

FIGURE 2 Typical U-shaped cleft palate I in a child with Pierre Robin

sequence.

Two (4%) patients were classified as grade 1, 20 (40%) were

grade 2, 20 (40%) as grade 3, and eight (16%) as grade 4.
Cleft widths ranged from 3 to 18 mm, with a mean value of
10.2 mm. The mean width of the U-formed clefts was 11.4
mm, and the mean width of the nonU-formed clefts was 7.8
mm.
Two-thirds (n 5 33) of the children had U-formed clefts
(Fig. 2) at the time of palatoplasty. The subgroup of children
with a U-formed cleft did not differ from the nonU-formed
subgroup in sex, birth weight, gestational age, congenital malformations, intrauterine impairment, severity of retro/micrognathia, or respiratory problems.
Thirty-one (62%) of the 50 children had isolated Pierre Robin sequence. Nineteen (38%) had other malformations besides
cleft and retro/micrognathia, with the Stickler syndrome with
myopia and a hereditary history being the most common (n 5
6; 12%). In five children (10%), the triad of Pierre Robin was
a minor feature in a complex malformation, each of these
unique. One child was diagnosed with velocardiofacial syndrome. The minor malformations consisted of one case of atrial septal defect, one case of ventricular septal defect (in the
child with fetal alcohol syndrome), two cases of hypospadias,
and three cases of different malformations of fingers or toes
(Table 2). Seventeen (34%) of the 50 children had some kind
of intrauterine impairment.
The average birth weight was 3100 g, compared with the
overall average in the Danish population of 3800 g. Fifteen
children (30%) were either small for date or preterm, four (8%)
were both preterm and small for date by obstetrical definitions,
six (12%) were just small for date, and five (10%) were just
preterm. Two children had an obstetrical diagnosis but were
neither small for date nor preterm; one had diabetic fetopathia,
and one had polyhydramnios. The other obstetrical diagnoses
recorded included one case of fetal alcohol syndrome, another
case of polyhydramnios, one case of gestational diabetes, three
cases of insufficient placenta, and one case of dizygotic twins.
None had a preterm diagnosis of oligohydramnios, but five

50

Cleft PalateCraniofacial Journal, January 2004, Vol. 41 No. 1

TABLE 2 Concommitant Malformations in 50 Pierre Robin

Children, Denmark, 1990 to 1999
Malformation

Cerebral ventricular tumor, mental retardation,

wide spinal canal at thoracic level, ventricular
septal defect, hypertelorism, strabismus, muscular hypotonia
Fusion of sixth and seventh costae, subcostal hernia bilaterally, inguinal hernia bilaterally, cavernous hemangioma
Paraxial hemimelia upper extremities bilateral,
low-set ears
Ventricular and atrial septal defects, esophageal
atresia, pulmonary stenosis
Mental retardation, muscular hypotony, hypospadias, seizures
Stickler syndrome
Velocardiofacial syndrome
Ventricular septal defect in fetal alcohol syndrome
Atrial septal defect
Four finger furrow bilateral
Polydactyly (dig. 1) manus bilateral
Fifth toe overlying fourth toe bilateral
Hypospadias

Designation

Number

Complex

Complex

Complex

Complex

Complex
Stickler
Minor
Minor
Minor
Minor
Minor
Minor
Minor

1
6
1
1
1
1
1
1
2

children, who were small for date, and two preterm children
had no obstetric diagnosis (Table 3).
There appears to be a connection between the severity of
respiratory problems and the degree of retro/micrognathia; the
smaller the jaw, the more severe respiratory problems. None
of the eight children with mild retro/micrognathia had severe
respiratory problems, 3 of the 19 children (16%) with moderate retro/micrognathia had severe respiratory problems, and
14 of the 23 children (61%) with severe retro/micrognathia
had severe respiratory problems (Fig. 3). There was no correlation among the grade, U-form, or width of the cleft with
the retro/micrognathia or the respiratory problems.
There was a positive correlation between the severity of
respiratory problems and children with malformations other
than the Pierre Robin triad. Approximately half (9/19) of the
children with other malformations had severe respiratory problems, compared with only one-fourth (8/31) of the children
with isolated Pierre Robin sequence.
The same tendency of more pronounced respiratory problems can be seen in the subgroup of patients with intrauterine
impairment, in which approximately half (8/17) had severe
respiratory problems, compared with only approximately onefourth (9/33) of the children with no report of intrauterine impairment.

TABLE 3 Intrauterine impairment in 50 Pierre Robin children,

Denmark 1990 to 1999
Obstetric diagnosis

Fetal alcohol syndrome

Insufficient placenta
Polyhydramnios
Dizygotic twin
Gestational diabetes
Insufficient placenta
None
Insufficient placenta
None
Diabetic fetopathia
Polyhydramnios

Designation

Preterm and small

Preterm and small
Preterm and small
Preterm and small
Preterm
Preterm
Preterm
Small for date
Small for date

for
for
for
for

Number

date
date
date
date

1
1
1
1
1
1
3
1
5
1
1

be performed; hence, only descriptive percentages and ratios

were stated and no significance values were calculated.
Using cleft palate as a primary inclusion parameter prevented us from theorizing about the children with possible
noncleft Pierre Robin. Indeed, a few children without cleft
have been referred to our clinic for surgical treatment (labioglosopexia) because of neonatal respiratory problems, and it
seems likely that there have been several children with similar
or less severe respiratory problems treated elsewhere.
In this study, we found a prevalence of Pierre Robin sequence of 1 in 14,000 live births, with a fairly stable occurrence ranging from two to seven cases per year.
Varying prevalences depending on the definition of Pierre
Robin ranging from 1 in 2000 to 1 in 30,000 live births have
been reported (Bush and Williams, 1983). One populationbased report found a prevalence of 1 in 9500, increasing to 1
in 8300 over a 23-year period (Bush and Williams, 1983). In
a Scandinavian study, a prevalence of Pierre Robin sequence
of 1 in 11,000 births was found (Kallen et al., 1996). Whether
these differences in prevalence, compared with the current
study, are caused by an imprecision in the recordings of these
large registries or a failure to include some cases in our clinical
series awaits further investigation.
In view of the very early reporting to our cleft registry, it
is not likely that early deaths in the population could explain
the lower prevalence found in the current study. Of course,

DISCUSSION
When defining a Pierre Robin population, it is necessary to
address not only the three main features of retro/micrognathia,
cleft palate, and respiratory problems but also concomitant
malformations or syndromes and possible intrauterine impairment.
The relatively small number (n 5 50) of patients with Pierre
Robin in this study limited the statistical analyses that could

FIGURE 3 Correlation between the degree of retro/micrognathia and the

severity of neonatal respiratory problems.

Printzlau and Andersen, PIERRE ROBIN SEQUENCE IN DENMARK

FIGURE 4 Comparison of cleft grading in the Pierre Robin population,

Denmark 1990 through 1999 with a Danish population of children without
Pierre Robin sequence (Jensen et al., 1988).

any stillborn child with Pierre Robin sequence would not have
been included in our study.
The incidence of isolated cleft palate in Denmark is 1 in
1500 live births (Christensen, 1999). Hence, approximately
10% of children with isolated cleft palate had the Pierre Robin
triad.
The U-shaped clefts were generally wider and longer, explaining the overall tendency of wider and longer clefts in the
Pierre Robin population, compared with a population of children with isolated cleft palate. The cleft grade in the Pierre
Robin population spans the whole spectrum, but there is a
tendency toward longer clefts in the children Pierre Robin,
compared with the total Danish isolated cleft palate population
studied in the period 1976 through 1981, in which 186 children
with isolated cleft palate including patients with Pierre Robin
were found (Jensen et al., 1988; Fig. 4). The same tendency
is seen in the cleft width measured at the time of primary
palatoplasty, in which the average width in a population-based
Finnish non-Pierre Robin isolated cleft palate population was
found to be 8.2 mm (Rintala et al., 1984), compared with an
average width of 10.2 mm in this study. The subgroup of Ushaped clefts in this study had an average width of 11.4 mm.
There was a correlation between the degree of retro/micrognathia and the severity of the neonatal respiratory problems.
This is in accordance with the theoretical pathogenesis of the
respiratory problems caused by a posterior displacement of the
base of the tongue leading to obstruction of the oropharynx,
i.e., true glossoptosis. However, there was no correlation between the cleft shape, width, or length with the degree of retro/
micrognathia, which might be expected from the theoretical
pathogenesis of palatal clefting because of the fetal obstruction
of the palatal fusion by the fetal tongue. This could indicate
either that the fetal degree of retro/micrognathia, supposedly
leading to a more pronounced cleft, is not necessarily in accordance with the neonatal degree of retro/micrognathia. It
might be theoretically imagined a fetal catch-up growth in
some patients. Still, the susceptibility and thus the severity of
the palatal cleft in the presence of fetal micrognathia might
vary depending on some other innate factors yet to be identi-

51

fied. Indeed, there are children born with even severe micrognathia who do not have cleft palate.
Few if any population-based clinical series of children with
Pierre Robin have been reported; hence, descriptions of concomitant or associated malformations and intrauterine impairment are sparse. Holder-Espinasse et al. (2001) and Shprintzen
(1992) have published some of the largest series of Pierre Robin sequence, but these were ascertained in highly specialized
treatment facilities as consecutive-case studies. In these studies
the rate of syndromic and obstetric cases was high. In our fullrange clinical series, 62% had isolated Pierre Robin sequence,
and only one-fourth of these had severe neonatal respiratory
problems, compared with approximately half of the children
with other malformations. The exact same tendency of more
pronounced respiratory problems was seen in the subgroup of
patients with intrauterine impairment. As a consequence, consecutive-case studies from specialized treatment facilities will
give a false impression of the severity and possible morbidity
and mortality of the Pierre Robin sequence.
In this study there were no fatal cases. In accordance with
the literature, it is not our impression that the Pierre Robin
sequence in itself carries a high risk of mortality when treated
in a specialized unit, but rather the possible concomitant malformations or dysfunctions of other organ systems seen in this
population.
On the basis of the wide clinical range of children with the
Pierre Robin triad, we developed a somewhat different treatment protocol, in which approximately one-third of the patients can be treated by specially trained cleft nurses in a home
setting, one-third of the patients require short- or long-term
supportive treatment with nasogastric tube feeding and nasal
airway in a pediatric unit, and the last one-third of the children
are treated surgically by a modified labioglossopexia. The level
of treatment depends on the severity of respiratory problems
and failure to thrive, as it was evaluated according to fixed
treatment goals. This treatment protocol is now the subject of
scientific evaluation.
CONCLUSION
The triad of Pierre Robin is not a nosological entity; it has
a diverse etiology and pathogenesis. As a clinician it is still
important to look on the triad of Pierre Robin as a clinical
entity. It can readily be defined at birth. The children experience the same kind of neonatal problems in varying degrees,
and in our clinic at the University Hospital of Copenhagen, it
has been possible to design an efficient treatment protocol.
Hence, epidemiological data are of interest, and we found
an incidence of 1 in 14,000 live births. In this population the
triad was seen most commonly as an isolated sequence but
also as part of complex syndromes and in children with different kinds of intrauterine impairment.
Seen from a syndromological point of view, the triad of
Pierre Robin can still in some cases be regarded as a syndrome,
sequence, or anomalad, depending on the individual case. The
triad can be seen with one of the features in a mild form and

52

Cleft PalateCraniofacial Journal, January 2004, Vol. 41 No. 1

either or both of the others in severe form, although there was

a correlation between severity of retro/micrognathia and severity of respiratory problems. There was a tendency of more
severe respiratory problems among children with either intrauterine impairment or other malformations in addition to the
Pierre Robin triad. It was not possible in this study to identify
subgroups within the population except for the Stickler and
velocardiofacial syndromes.
REFERENCES
Bush PG, Williams AJ. Incidence of Pierre Robin anomalad (Pierre Robin syndrome). Br J Plast Surg. 1983;36:434437.
Caouette-Laberge L, Bayet B, Larocque Y. The Pierre Robin sequence: review
of 125 cases and evolution of treatment modalities. Plast Reconstr Surg.
1994;93:934942.
Christensen K. The 20th century Danish facial cleft populationepidemiological and genetic-epidemiological studies. Cleft Palate Craniofac J. 1999;36:
96104.
Cohen MM Jr. Robin sequences and complexes: causal heterogeneity and pathogenetic/phenotypic variability. Am J Med Genet. 1999;84:311315.
Cohen MM Jr. Syndromology: an updated conceptual overview. IV. Perspectives on malformation syndromes. Int J Oral Maxillofac Surg. 1989;18:286
290.

Hanson JW, Smith DW. U-shaped palatal defect in the Pierre Robin anomalad:
developmental and clinical relevance. J Pediatr. 1975;87:3033.
Holder-Espinasse M, Abadie V, Cormier-Daire V, Beyler C, Manach Y, Munnich A, Lyonnet S, Couly G, Amiel J. Pierre Robin sequence: a series of
117 consecutive cases. J Pediatr. 2001;139:588590.
Jensen BL, Kreiborg S, Dahl E, Fogh-Andersen P. Cleft lip and palate in Denmark, 19761981: epidemiology, variability, and early somatic development.
Cleft Palate J. 1988;25:258269.
Kallen B, Harris J, Robert E. The epidemiology of orofacial clefts. 2. Associated malformations. J Craniofac Genet Dev Biol. 1996;16:242248.
Lary JM, Paulozzi LJ. Sex differences in the prevalence of human birth defects:
a population-based study. Teratology. 2001;64:237251.
Rintala A, Ranta R, Stegars T. On the pathogenesis of cleft palate in the Pierre
Robin syndrome. Scand J Plast Reconstr Surg. 1984;18:237240.
Robin P. Glossoptosis due to atresia and hypotrophy of the mandible. Am J Dis
Child. 1934;48:541547.
Sher AE. Mechanisms of airway obstruction in Robin sequence: implications
of treatment. Cleft Palate Craniofac J. 1992;29:224231.
Shprintzen RJ. Pierre Robin, micrognathia and airway obstruction: the dependency of treatment on accurate diagnosis. Int Anesthesiol Clin. 1988;26:65
71.
Shprintzen RJ. The implications of the diagnosis of Robin sequence. Cleft Palate Craniofac J. 1992;29:205209.
Smith DW. Classification, nomenclature and naming of morphologic defects. J
Pediatr. 1975;87:162164.