The Cleft Palate–Craniofacial Journal 52(6) pp. 732–742 November 2015 Ó Copyright 2015 American Cleft Palate–Craniofacial Association

ORIGINAL ARTICLE Multidisciplinary Aspects of 104 Patients With Pierre Robin Sequence Charles Filip, M.D., Ph.D., Kristin Billaud Feragen, Clin.Psychol., Ph.D., Jorunn Skartveit Lemvik, M.S., Nina Lindberg, R.N., M.Sc., Els-Marie Andersson, D.D.S., Ph.D., Mitra Rashidi, M.D., Michael Matzen, M.D., D.D.S., Hans Erik Høgevold, M.D., D.D.S., Ph.D. Objective: To describe Pierre Robin sequence patients with a cleft palate from a multidisciplinary perspective. Patients: A total of 104 individuals with Pierre Robin sequence and cleft palate, born between 1980 and 2010. Method: Data were collected retrospectively and compared with large control groups. Results: Of 104 patients, 19 (18.3%) were treated with a nasopharyngeal or oropharyngeal tube, continuous positive airway pressure, and/or a tracheotomy. The mean weight percentile for newborns with Pierre Robin sequence was 30.9. It decreased to 29.9 at the time of cleft palate repair (mean age, 13.7 months) (P ¼ .78). Of 87 patients, 30 (34.5%) developed normal speech after cleft palate repair. Of 93 nonsyndromic Pierre Robin sequence patients, 31 (33.3%) had or are having surgery for velopharyngeal insufficiency, a rate that is significantly higher when compared with a control group of cleft palate–only patients (19.4%; P ¼ .004). Of 31 patients, 25 (80.6%) developed normal resonance after surgery for velopharyngeal insufficiency. There was no significant difference in the rate of syndromes between the Pierre Robin sequence patients and a control group of cleft palate patients without Pierre Robin sequence (P ¼ .25). Seven of 39 boys (17.9%) with Pierre Robin sequence had a diagnosis of autism spectrum disorder. Conclusion: Even though the mean weight percentile for newborns with Pierre Robin sequence was low, the patients did not show a growth spurt during the first year of life. The high rate of velopharyngeal insufficiency after cleft palate repair in patients with Pierre Robin sequence needs further investigation. Also, the high rate of autism spectrum disorder among boys with Pierre Robin sequence prompts further investigation. KEY WORDS:

cleft palate, fistula, growth, Pierre Robin sequence, psychology, speech, VPI

In 1923 Pierre Robin, a Parisian stomatologist, described a range of findings consisting of breathing problems in patients with glossoptosis and associated micrognathia. In 1934, he stated that patients with the findings he had previously described (1923) could also have cleft palate (CP). Hanson and Smith (1975) noted that the anomalies described by Robin (1923, 1934) occur as a developmental sequence, but they used the term Robin anomalad. The term sequence was suggested by Carey et al. in 1982. Breugem and Mink van der Molen (2009) emphasized the original definition by Pierre Robin consisting of micrognathia, glossoptosis, and airway compromise in diagnosing the sequence. Due to abnormal mandibular outgrowth (micrognathia), the tongue stays high and retroposed and impinges against the nasopharynx, causing breathing problems and impeding feeding. The prevalence is highly variable, estimated to be between 1 in 2000 to 1 in 30,000 (Bush and Williams, 1983; Caouette-Laberge et al., 1994), which may be due to the high number of definitions for the sequence. Andersson et al. (2010a) found the prevalence of

Dr. Filip is Head, Cleft Lip and Palate Unit, Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Rikshospitalet; Dr. Billaud Feragen is Clinical Psychologist, Cleft Lip and Palate Unit, Department of Speech and Language Disorders, Statped sørøst; Mrs. Lemvik is Speech and Language Therapist, Cleft Lip and Palate Unit, Department of Speech and Language Disorders, Statped sørøst; Mrs. Lindberg is Specialist Nurse, Cleft Lip and Palate Unit, Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Rikshospitalet; Dr. Andersson is Consultant Orthodontist, Cleft Lip and Palate Unit, Department of Odontology, Oslo University Hospital, Rikshospitalet; Dr. Rashidi is Senior Registrar, Cleft Lip and Palate Unit, Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Rikshospitalet; Dr. Matzen is former Head, Cleft Lip and Palate Unit, Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Rikshospitalet; and Dr. Høgevold is Consultant Plastic Surgeon, Cleft Lip and Palate Unit, Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway. Parts of this study were presented orally at the Annual Scientific Conference of The Craniofacial Society of Great Britain & Ireland, Oxford, United Kingdom, April 7–8, 2014; and at the 25th Annual European Association of Plastic Surgeons Meeting, Lacco Ameno, Italy, May 29–31, 2014. Submitted June 2014; Revised September 2014; Accepted September 2014. Address correspondence to: Dr. Charles Filip, Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Rikshospitalet, Postboks 4950 Nydalen, 0424 Oslo, Norway. E-mail cfi[email protected].

DOI: 10.1597/14-161 732

Filip et al., MULTIDISCIPLINARY ASPECTS OF PIERRE ROBIN SEQUENCE

Pierre Robin sequence (PRS) among 994 patients with clefts of the secondary palate who were born between 1960 and 2002 to be 11.7%. The literature on PRS is still scarce, and there are few studies describing individuals with PRS from a multidisciplinary perspective. Management of patients with PRS is still controversial and often differs significantly across teams and treatment centers (Han et al., 2013). The aim of this retrospective study was to describe 104 individuals, born with PRS and CP over a 33-year period, from a multidisciplinary perspective.

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born at term (Juliusson et al., 2009). For patients born before gestational week 37, a growth chart for assessing fetal growth was used (Johnsen et al., 2006). Weight was available and recorded at birth for 84 patients and at the time of palate repair for 96 patients. Eight of 104 patients (7.7%) were born preterm (i.e. prior to 37th week of gestation). Feeding difficulties (prolonged meals, vomiting, reflux, abdominal pains, choking and ‘‘struggle with feeding’’) were recorded. Cleft Palate

MATERIAL

AND

METHODS

Cleft care in Norway has for more than 50 years been centralized between two multidisciplinary teams, one in Oslo and one in Bergen. Standardized follow-up was introduced in Oslo in the early 1960s (Andersson et al., 2010a). This multidisciplinary study involved specialists from five disciplines (plastic surgery, psychology, orthodontics, speech and language therapy, and nursing) and included information about respiratory interventions, growth and feeding, CP severity, type of CP repair, surgery for velopharyngeal insufficiency (VPI), speech difficulties, oronasal fistulae, syndromes and genetic mutations, conditions affecting cognitive and/or psychological function, and overall psychological adjustment. Patients Inclusion criteria for the study were birth between 1980 and 2010, micrognathia, glossoptosis, CP, and respiratory obstruction in the neonatal period. A total of 107 consecutive patients with a CP as an associated anomaly to PRS were identified as meeting the inclusion criteria for participation in the study. Primary palate surgery was performed at the Cleft Lip and Palate Unit, Oslo University Hospital (CLPU-OUH). Three patients had to be excluded because address information was missing for two and one patient declined participation in the study. Data were collected retrospectively from the archives of the CLPU-OUH. Respiratory Intervention Frequency and type of respiratory interventions were recorded. The rate of respiratory interventions in syndromic PRS patients was compared with nonsyndromic PRS patients. Growth and Feeding Birth weight and weight at the time of CP repair were recorded. Growth curves for Norwegian children aged 0 to 1 year and 1 to 5 years were used for patients

Cleft palate was classified by cleft severity, as described by Andersson et al. (2010a) (Fig. 1). Classification of the cleft severity was made by the surgeon at the primary operation and was compared with a control group consisting of 872 patients born between 1960 and 2002 with clefts of the secondary palate without PRS who were treated at the CLPUOUH (Table 1). The type of CP repair was recorded. In 1996 the CLPU-OUH changed the CP repair from a modified von Langenbeck (1861) to a Sommerlad repair (Sommerlad et al., 1994). The modified von Langenbeck repair included repositioning of the levator veli palatine muscle, but not as radical as that performed in a Sommerlad repair. Cleft palate re-repairs were also recorded. Follow-up information to 16 years of age was recorded from the files at the CLPU-OUH. VPI Surgery Superiorly based pharyngeal flaps and sphincter pharyngoplasties (Abyholm et al., 2005), as well as autologous fat transplantations (Filip et al., 2013) were recorded. The rate of VPI surgery in nonsyndromic PRS patients was compared with that of a control group consisting of 351 nonsyndromic, non-PRS patients born with a cleft of the secondary palate between 1968 and 1999 and treated at the CLPU-OUH. The rates of VPI surgery in the study group were analyzed for a modified von Langenbeck repair versus a Sommerlad repair; different cleft types; and for the presence versus the absence of a syndrome. Speech The speech files contained perceptual speech assessments performed over a long time span. Different speech therapists, who specialized in cleft palate speech and were part of the cleft team, had assessed the patients. If a speech disorder was present at any of the assessments, it would be registered in the study. Hence, the speech results reflect a general risk of developing

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speech disorders irrespective of the final results, which may be influenced by, for example, time, speech therapy, and/or VPI surgery. Speech results were dichotomized for the two variables VPI and Cleft Speech Characteristics. Velopharyngeal Insufficiency Hypernasality, audible nasal emission, and/or velar turbulence were registered as present or absent and pooled into the parameter VPI. These speech disorders can be said to represent passive speech difficulties reflecting structural/functional limitations in the velopharynx (Chapman and Willadsen, 2011). Speech results for the variable VPI were available and recorded for 87 patients. Cleft Speech Characteristics Active cleft-related speech difficulties (Chapman and Willadsen, 2011; Klinto et al., 2011) such as retracted articulation, glottal articulation, nasal realization of /s/, and other cleft-related s-deviations formed the variable Cleft Speech Characteristics and were available and recorded for 90 patients. Oronasal Fistulae Frequency of oronasal fistulae was recorded and compared with that of a control group consisting of 878 patients born between 1960 and 2002 with a cleft of the secondary palate without PRS and treated at the CLPUOUH. Genetics Frequency and type of syndromes, as well as genetic mutations, were recorded when diagnosed by a clinical geneticist. The rate of syndromes was compared with that of a control group consisting of 878 patients born between 1960 and 2002 with a cleft of the secondary palate without PRS and treated at the CLPU-OUH. (Referral of all newborns with PRS to a geneticist was introduced in the CLPU-OUH in 2008.) Psychological Aspects

FIGURE 1 Classification of cleft palate (CP). The extent of the CP was divided into five grades: grade 0: submucous CP; grade 1: soft palate; grade 2: less than one third of the hard palate; grade 3: more than one third of the hard palate up to subtotal; and grade 4: total, cleft extending to the incisive foramen.

Psychological assessments have been performed systematically at age 10 since 2002 and also at age 16 since 2004. Hence, psychological data did not exist for patients born before 1988 or after 2003. As a result, data on psychological adjustment were available for 51 patients aged 10 years and 40 patients aged 16 years at the time of assessment. Some patients had undergone psychological assessments at ages 10 and 16. Hence, the total number of participants was 82. Results were

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TABLE 1 Study Population: 104 Individuals With Pierre Robin Sequence (PRS) Born Between 1980 and 2010 and Treated at the Cleft Lip and Palate Unit–Oslo University Hospital Severity of Clefts in Control Group* Characteristic

n

%

Gender Male Female Total

51 53 104

49.0 51.0

Severity of clefts Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Total

3 26 23 30 22 104

2.9 25 22.1 28.8 21.2

Type of cleft palate primary repair Modified von Langenbeck repair Sommerlad repair

38 66

36.5 63.5

Distribution of VPI surgery (performed or on waiting list) in clefts with Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Total

2 7 12 11 4 36

66.7 26.9 52.2 36.7 18.2

P . .096

Distribution of VPI surgery (performed or on waiting list) following Modified von Langenbeck repair Sommerlad repair

13 23

34.2 34.8

P ¼ .95

VPI surgery (performed or on waiting list) Pharyngeal flap Sphincterplasty Autologous fat transplantation

33 2 1

31.7 1.9 0.96

Distribution of genetic aspects Syndromic Nonsyndromic Genetic mutation (not part of a syndrome)

11 93 6

10.6 89.4 5.8

Distribution of VPI surgery (performed or on waiting list) in Syndromic Nonsyndromic

5 31

45.5 33.3

2 8 8 6

1.9 7.7 7.7 5.8

3 16

27.3 20.8

Respiratory treatment Oropharyngeal tube Nasopharyngeal tube CPAP Tracheotomy Distribution of respiratory intervention in Syndromic Nonsyndromic

n

%

233 372 115 89 63 872

26.7 42.7 13.2 10.2 7.2

P ¼ .42

P ¼ .41

* Control group consisted of 872 non-PRS patients born with clefts of the secondary palate between 1960 and 2002, treated at the Cleft Lip and Palate Unit–Oslo University Hospital.

compared with children with a CP without PRS from the same birth cohorts (n ¼ 370). Psychological assessments included the Personality Inventory for Children (PIC), Satisfaction With Appearance (SWA), and the Hopkins Symptom Checklist25 (HSCL-25). Personality Inventory for Children The PIC (Wirt, 1981) is a multidimensional personality inventory and was administered at age 10, using the

child’s mother as the informant. The PIC provides an empirical classification based on 12 clinical scales, placing a T-value within the category of mild, moderate, or severe problems. The scales that were used in the present study were the Adjustment scale and the Intellectual Screening scale. The Intellectual Screening scale has been reported to correlate .55 with the Full Scale IQ on the Wechsler scales (Wirt, 1981). A Norwegian version of the instrument was used (Troland, 1988).

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Satisfaction With Appearance The SWA (developed by the Psychology Special Interest Group of the Craniofacial Society of Great Britain and Ireland) reflects satisfaction with cleftrelated and noncleft-related parts of the face, speech, overall appearance, and visibility of cleft. Each rating is made on an interval scale of 0 to 10, where a score of 10 indicates very high levels of satisfaction with appearance. A 12-item version of the scale was used at age 10; whereas, four items were administered at age 16. Mean total scores were calculated. The SWA has been reported to possess satisfactory internal consistency and a coherent factor structure (Emerson et al., 2004). The Cronbach a was .89 in the present study. Hopkins Symptom Checklist The shortened version of the Hopkins Symptom Checklist, the HSCL-25 (Kandel and Davies, 1982), is a well-known and widely used screening instrument that is meant to identify common symptoms of depression and anxiety, such as self-identified problems with sleep or lack of interest. The HSCL-25 was used at age 16 and measures depressive symptoms using seven items. Tambs and Moum (1993) have demonstrated that this abbreviated version of the instrument correlated well (r ¼ .92) with the HSCL. Each item ranges from Never (1) to Very much (4). Mean scores were calculated. Severity of symptoms are categorized using cutoff scores, where mean scores below 1.75 indicate no or mild frequency of symptoms, values between 1.75 and 2.00 indicate moderate problems, and mean scores above 2.00 are indicative of severe symptoms (Rognerud et al., 2002). Within the study sample, the HSCL-7 showed high internal consistency reliability (Cronbach a ¼ .84). Statistical Analysis Chi-square tests were used to analyze differences in frequency between groups regarding rates of respiratory interventions, VPI, VPI surgery, syndromes, fistulae, and conditions affecting psychological and/or cognitive function. Percentiles at birth were compared with percentiles at CP repair with paired-sample t tests; whereas, differences between groups on the psychological outcome measures were analyzed using independent-sample t tests. P values , .05 were considered to be significant. Ethical Approval The study was approved by the Regional Ethics Committee of Southern Norway.

RESULTS Descriptive data of the study sample are presented in Table 1. The mean age of the study group was 15.6 (range, 3.3 to 33.4) years. Four patients were below 4 years of age. Respiratory Intervention Two patients were treated with an oropharyngeal tube from 4 days to 6 months; eight patients with a nasopharyngeal tube from 2 to 150 days, and eight patients with continuous positive air pressure (CPAP) from a few days to 1 year. Six patients underwent a tracheotomy, which was performed in the neonatal period in five of six patients and was left in place at least until the CP was repaired in four of six patients. One patient still has a tracheostomy at the age of 3 years. Nineteen patients (18.3%) were treated with an oropharyngeal or nasopharyngeal tube, CPAP, and/or a tracheotomy (Table 1). There was no significant difference between syndromic and nonsyndromic PRS patients in the rate of these treatments combined (P ¼ .41). Prone positioning had been applied in the majority of patients. Its efficiency had not been documented consequently. None had been treated with mandibular distraction or tongue fixation. Growth and Feeding The mean weight percentile for newborns with PRS was 30.9 (n ¼ 78). It decreased to 29.9 at the time of CP repair (mean age, 13.7 months), a difference that was not statistically significant (P ¼ .78). During the neonatal period, feeding difficulties appeared in 64 of 94 patients (68.1%). Of 70 patients, 40 (57.1%) were fed with a nasogastric tube, often in addition to bottle feeding. One patient required a percutaneous endoscopic gastrostomy. Thirty patients (42.9%) were bottle fed only. None of the patients was breastfed. At the time of CP repair, 12 of 101 patients (11.9%) had feeding difficulties. Five (5.0%) were fed with a nasogastric tube and two (2.0%) required a percutaneous endoscopic gastrostomy. Two (2.0%) were bottle fed only. Cleft Palate Repair Thirty-eight patients (36.5%) underwent a modified von Langenbeck CP repair and 66 (63.5%), a Sommerlad CP repair (Table 1). Patients born from 1980 to 1995 almost always underwent a modified von Langenbeck repair at 15 to 18 months of age; and those born from 1996 to 2010, a Sommerlad repair at 12 months of age. The mean age at CP repair for the whole group was 14.5 6 6.5 months. Two patients (1.9%) had re-repairs

Filip et al., MULTIDISCIPLINARY ASPECTS OF PIERRE ROBIN SEQUENCE

secondary to wound dehiscence, performed at the age of 3 and 4 years, respectively, and were not included in the VPI surgery group. VPI Surgery A superiorly based pharyngeal flap was the most commonly performed surgery for VPI (Table 1). Of 28 pharyngeal flaps, 1 (3.6%) had to be redone due to wound dehiscence. Of 93 nonsyndromic PRS patients in our study, 31 (33.3%) had or are having surgery for VPI. This rate was significantly higher when compared with that of the control group of CP-only patients, in which 68 of 351 (19.4%) had undergone surgery for VPI (P ¼ .004). There was no significant difference between the rate of VPI surgery after a modified von Langenbeck repair and that after a Sommerlad repair (P ¼ .95). In addition, there was no significant difference between the rate of VPI surgery when different cleft types were compared (P . .096). Nor was there a significant difference in the rate of VPI surgery when syndromic PRS patients were compared with nonsyndromic PRS patients (P ¼ .42). Five of 11 syndromic PRS patients (45.5%) and 31 of 93 nonsyndromic PRS patients (33.3%) are undergoing or have undergone VPI surgery (Table 1). Speech Thirty-four of 87 patients (39.1%) were registered with both active and passive speech disorders after CP repair. Thirty of 87 patients (34.5%) developed normal speech after CP repair. Velopharyngeal Insufficiency Fifty of 87 patients (57.5%) were registered with VPI after CP repair. Speech improved in all patients after VPI surgery. Twenty-five of 31 patients (80.6%) developed normal resonance after VPI surgery; 3 of 31 patients (9.7%) had some persistent velar turbulence, but no hypernasality 12 months postoperatively; 3 of 31 patients (9.7%) had reduced hypernasality postoperatively, though resonance was still not quite in the normal range. Cleft palate severity had no significant effect on VPI, for either the nonsyndromic (P ¼ 1.00) or the syndromic patients (P ¼ 1.00). Cleft Speech Characteristics Forty-two of 90 patients (46.7%) were registered with cleft speech characteristics after CP repair. Cleft palate severity did not significantly affect articulation errors (P ¼ .16).

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Oronasal Fistulae Five patients (4.8%) developed an oronasal fistula after CP repair. Three of these were repaired. Two asymptomatic fistulae were left unrepaired. There was no significant difference in the rate of fistulae between the study group and the control group of CP patients without PRS (P ¼ .73). Of 878 patients, 36 (4.1%) developed an oronasal fistula in the control group. Genetics Eleven patients (10.6%) were diagnosed with a syndrome. Another six (5.8%) patients had a genetic mutation that was not part of a syndrome. Stickler was the most common syndrome, with five affected patients (4.8%). Two patients (1.9%) were diagnosed with Marshall syndrome; one patient with the 22q11.2 deletion syndrome; one with fragile X syndrome; one with oculo-auriculo-vertebral spectrum disorder; and one with campomelic dysplasia. None of the 15 patients born from 2008 to 2010 had been diagnosed with a syndrome as of May 2014. There was no significant difference in the rate of syndromes between the study group and the control group of CP patients without PRS (P ¼ .25). Of 878 patients, 65 (7.4%) had a syndrome diagnosed in the control group. Psychological Aspects A total of 51 of the 82 patients with PRS (62.2%) had an additional condition expected to affect psychological and/or cognitive function (such as a developmental disability, learning difficulties, attention/hyperactivity disorder, an autism spectrum disorder [ASD], dyslexia); whereas, this was the case for 145 of the 370 patients with CP without PRS (39.2%). This difference was statistically significant (P ¼ .001). When exploring the type of additional conditions, it appeared that seven of the patients with PRS (9.1%) had a diagnosis of ASD, compared with 1.1% (4 of 370) of the children with a CP (P ¼ .001). The patients with PRS had a significantly higher frequency of ASD whether they had a diagnosed syndrome (12.5%, 2 of 16) or not (9.4%, 5 of 54). All the children with PRS and a diagnosis of ASD were boys; 17.9% (7 of 39) of the boys with PRS had a diagnosis of ASD compared with 2.3% (4 of 172) of the boys with a CP in the control group (P ¼ .001). In terms of psychological adjustment, there were no significant differences between patients with PRS and patients with CP only. Children with CP with and without PRS had adjustment scores within the normal range on the PIC (CP: 55 6 12.80; PRS: 54 6 13.05; t166

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¼ 0.36, P ¼ .76). The Intellectual Screening scale revealed no differences between the two groups (CP: 68 6 23.52; PRS: 70 6 26.41; t166 ¼ 0.34, P ¼ .76). Both groups had scores reflecting the presence of cognitive difficulties for some of the patients. These were expected findings, given the high frequency of additional conditions in children with CP and PRS. In terms of satisfaction with appearance, according to SWA measurements, the children with PRS appeared to be somewhat less satisfied with appearance (8.2 6 1.62) compared with the children with CP (8.5 6 1.54). However, this difference was not statistically significant (t221 ¼ 0.43, P ¼ .43). When exploring specific items, it appeared that patients with PRS were less satisfied with their overall appearance, face, profile, teeth, and speech, but none of these differences were statistically significant. When measured at adolescence, there was still no statistically significant difference on the total SWA score (t161 ¼ 0.03, P ¼ .93). Adolescents with PRS reported few depressive symptoms (1.61 6 0.61) as those with CP only (1.60 6 0.56; t204 ¼ 0.34, P ¼ .96), and both groups were within the normal range. Within the PRS group, patients with an additional condition (PRSþ) such as a diagnosed syndrome, dyslexia, developmental difficulties, or ASD, had significantly more adjustment problems than patients with PRS only (PRS: 48 6 5.92; PRSþ: 62 6 16.71; t23 ¼ 2.88, P ¼ .008). As expected, children with PRSþ also had higher mean scores on the Intellectual Screening scale, indicating significant cognitive difficulties (PRS: 56 6 11.09; PRSþ: 90 6 30.32; t23 ¼3.94, P ¼ .001). As can be seen from the standard deviation, there were large variations in level of cognitive problems in the PRSþ group, ranging from normal to severe problems. There were no differences between patients with PRS and PRSþ regarding satisfaction with appearance at age 10 (P ¼ .37) or 16 (P ¼ .86) nor any differences in depressive symptoms (P ¼ .15). DISCUSSION This is a multidisciplinary study of 104 patients with PRS and CP describing the management and outcome of treatment performed at a tertiary center in Norway.

reliably commented on. In comparison, retrospective chart reviews from Cleveland, Ohio, and San Diego, California, showed that 77 of 125 PRS patients (62%) were treated with prone positioning; tracheotomy had been performed in 10%, mandibular distraction in 9%, mandibular distraction and tracheostomy in 3%, tongue-lip adhesion in 6%, and nasopharyngeal tube inserted in 3% (Izumi et al., 2012). The growth analysis in this study showed that an expected increase in growth during the first year was absent, demonstrated by the percentiles at birth compared with percentiles at the time of CP repair (P ¼ .78). This raises the question of whether respiratory (and feeding) interventions were adequate. Polysomnography (PSG) has not been standardized to infants with PRS in Norway. Anderson et al. (2011) registered PSGs in patients with PRS who received care at the Johns Hopkins Hospital in their first year of life, prior to any surgical airway intervention. Obstructive sleep apnea was identified in 11 of 13 patients (85%). The high incidence of obstructive sleep apnea in this group suggests that PSG should be performed early in children with PRS. We are currently in the process of revising our guidelines to include close observations of oxygen saturations, transcutaneous carbon dioxide levels, and base excess, as well as stricter use of nasopharyngeal airways (Singer and Sidoti, 1992; Wagener et al., 2003; Anderson et al., 2007) in the newborn with PRS. Prospective trials are needed to determine the issues of when and which respiratory interventions should be used. We found no significant difference in the rate of respiratory interventions (oropharyngeal or nasopharyngeal tube, CPAP, tracheotomy) between syndromic and nonsyndromic PRS patients, which runs parallel to the findings of Meyer et al. (2008), who found no significant differences between children with isolated PRS and those with PRS and a syndrome or a neurologic-related comorbidity with regard to any interventions required to maintain a patent airway. However, Izumi et al. (2012) found that PRS patients with syndromic features required more aggressive airway management. Growth and Feeding

Respiratory Intervention Airway compromise is the most important issue for a patient with PRS. However, relatively few of our patients received invasive therapy for respiratory difficulties, with 18% being treated with either a nasopharyngeal tube, an oropharyngeal tube, CPAP, and/or a tracheotomy. Most patients were treated with prone positioning only, but its efficiency has not been adequately documented and therefore can not be

The weight at birth and at the time of CP repair were significantly lower in the study group compared with the Norwegian population. Furthermore, Printzlau and Andersen (2004) found the birth weight to be lower in PRS neonates when compared with the Danish population. The participants in the present study seemed to follow their own growth curves. However, they did not show a growth spurt during the first year of life, despite a decline in feeding difficulties.

Filip et al., MULTIDISCIPLINARY ASPECTS OF PIERRE ROBIN SEQUENCE

In our study, eight (7.7%) were born preterm, which is similar to the incidence in the Norwegian population as a whole, where 7.5% of newborns are born preterm (Markestad and Halvorsen, 2007). The high incidence of feeding difficulties and the requirement of supplementary feeding in patients with PRS are in line with other studies (Printzlau and Andersen, 2004; Reid et al., 2006; Evans et al., 2011; Glynn et al., 2011). Though the incidence of feeding difficulties seemed to decrease at the time of CP repair, 11.9% were still struggling with feeding at this age. Furthermore, Reid et al. (2006) found that children with PRS may require feeding support beyond 14 months of age, which was in contrast to children with CP without PRS (with or without cleft lip). In the latter, feeding difficulties were resolved by 3 months of age. The findings indicate that systematic follow-up is needed with regard to growth, feeding, and development in children with PRS. Cleft Palate and VPI Surgery Nonsyndromic PRS patients had a significantly higher rate of VPI surgery compared with the control group of CP-only patients. Of the nonsyndromic PRS patients, 33% had or are having VPI surgery compared with 19% who had VPI surgery in the control group. This could have been influenced by the severity of clefts, given that PRS patients had a larger distribution of more severe clefts compared with the control group (Table 1). However, this could not be confirmed when the rate of VPI surgery was correlated to the severity of clefts in the PRS study group. Stransky et al. (2013) found no significant difference in the rates of VPI surgery between 55 nonsyndromic PRS patients and 129 CP-only patients. However, the PRS group had a resonance that was significantly worse. Goudy et al. (2011) found no significant difference in the need for surgical correction of VPI between a group of 21 nonsyndromic PRS patients and 42 CP-only patients. Andersson et al. (2010b), however, found the incidence of pharyngoplasty among patients with CP only, treated at the CLPU-OUH, to be significantly associated with the severity of clefts. Children with total clefts of the secondary palate were more likely to require pharyngoplasty than children with clefts of the soft palate alone. We did not find any significant difference in the rate of VPI surgery between syndromic and nonsyndromic PRS patients. Surprisingly, Witt et al. (1997) found a significantly increased rate of surgery for VPI in nonsyndromic PRS patients compared with syndromic PRS patients (P ¼ .003). The rate of syndromes in the PRS group was 41%, compared with 10.6% in the present study. We did not find any significant difference in the rate of VPI surgery after the two different CP repairs (i.e., a

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modified von Langenbeck repair performed at 15 to 18 months of age, compared with a Sommerlad repair at 12 months of age). It is interesting that Nyberg et al. (2010) found no significant differences in speech outcomes after palatoplasty with or without a radical intravelar veloplasty. However contradictory, the number of velopharyngeal flaps was significantly lower when using a radical intravelar veloplasty, and therefore, it was decided to continue with the latter technique for primary palate repair until a larger comparative study has been performed. The rate of VPI surgery should never be interpreted as being equivalent to ‘‘speech outcome.’’ There are major factors that influence the rate of VPI surgery, such as the threshold for performing it. That threshold was most likely lowered in our department during the study period, because we no longer accept even milder symptoms of VPI, which would negatively influence the rate of VPI surgery after a Sommerlad repair compared with that of a modified von Langenbeck repair. Also, four patients were below 4 years of age at the time of the current study, and their need for VPI surgery cannot be concluded as yet, which, on the other hand, could benefit the results of a Sommerlad repair. In addition, relatively big differences in the thresholds for performing VPI surgery are expected between cleft centers. Hence, intercenter comparisons cannot be made reliably. As already mentioned, we found a difference in the distribution of CP severity in the PRS population compared with the control group. This finding should be confirmed in future studies. Speech The high rate of VPI and Cleft Speech Characteristics in the current study might not be fully representative, because a speech disorder at any assessment after CP repair was registered. Lohmander (2011) reported that speech disorders decrease with age. Still, with a high recorded rate of persistent VPI after CP repair, 80.6% developed normal resonance after VPI surgery. Cleft palate severity did not affect speech outcome in the current study, which runs parallel to the correlation between CP severity and rate of VPI surgery mentioned in the previous section. Nyberg et al. (2010) found a cleft involving soft and hard palates to result in a more deviant speech than a cleft soft palate. Oronasal Fistulae We found no significant difference in the rate of oronasal fistulae when the PRS patients were compared with the control group of CP patients without PRS; it was relatively low in both groups (4.8% versus 4.1%).

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The rates of fistulae vary in the literature from 3% (Wilhemi et al., 2001) to 45% (Rohrich and Byrd, 1990). Genetics We found no significant difference in the rate of syndromes when the PRS patients were compared with the control group of CP patients without PRS. In a systematic literature review from 2012 by Izumi et al., 391 of 1282 patients (30.5%) with PRS had been diagnosed with a syndrome. Stickler syndrome was the most common, reported in 180 of the total cases (14%). This is in contrast to our cohort of PRS patients in which a syndrome had been identified in 11 cases (10.6%) and Stickler syndrome in five (4.8%). The reason behind the relatively low number of syndromes in our cohort is not clear. Referral of all newborns with PRS to a geneticist was introduced in the CLPU-OUH in 2008. However, none of the 15 children born from 2008 to 2010 in our study cohort have yet been diagnosed with a syndrome. Psychological Aspects Mean scores revealed that the participants with PRS were not at significantly greater psychological risk than CP children without PRS. We find it interesting that analyses pointed to a strong association between boys with PRS and a diagnosis of ASD, a finding also reported by Feragen et al. (2014). The group of children with PRS and an additional condition were showed to be at psychological and cognitive risk, as has been reported in children with CP who also have an additional condition (Feragen and Stock, 2014) and also has been described in meta-analyses of children with chronic conditions (Lavigne and Faier-Routman, 1992; Martinez et al., 2011). Children with a CP alone, with or without PRS, had scores within the normal range and similar to those of nonclinical comparison groups. The present study found a disturbingly high frequency of ASD in male patients with PRS (17.9%) as compared with 2.3% of the boys with CP only. A morbidity survey from 2007 (Brugha, 2009) reported prevalence rates of 1.8% in boys, which is comparable to what was found in the control group. However, the finding that almost one fifth of the male patients with PRS had a diagnosis of ASD should be investigated further. Future studies should explore whether the present findings suggest a genetic double association not yet identified, or whether there could be other causal links between ASD and PRS. Autism spectrum disorders appear to be more common among boys than girls. A Scandinavian population study of Asperger syndrome in school

children found a male to female ratio of 4:1 (Ehlers and Gillberg, 1993); whereas, another study reported as many as 15 times more males than females (Wing, 1981). The finding regarding only boys being affected with ASD in the present study could therefore be explained by an expected male to female ratio. Strengths and Weaknesses of the Study The strength of the present study is its sample size and its excellent participation rate. Standardized follow-up of cleft patients was introduced in Oslo in the early 1960s, providing the opportunity for collecting consecutive data with minimal loss of information. In addition, the sample was based on consecutive cases within a centralized treatment setting, strengthening the sample’s representativeness. The study’s multidisciplinary perspective also provided a broader approach to the treatment of patients with PRS. The retrospective design of the current study, however, was a limitation, because relevant data was in some cases lost or missing. In addition, when exploring differences between some of the subgroups within the total sample (such as syndromes or speech variables), statistics revealed nonsignificant results. Larger samples are needed in order to confirm the present findings. CONCLUSION We found no significant difference in the rate of respiratory interventions between syndromic and nonsyndromic PRS patients. Prospective trials are needed to determine the issues of when and which respiratory intervention should be used. Systematic follow-up and a national standard is needed for children born with PRS with regard to feeding and growth. Patients with PRS and a CP were in a low weight percentile at birth. They followed their growth curves until the time of CP repair but showed no growth spurt in the first year of life. Of 87 patients with PRS, 50 were registered with VPI after CP repair. Patients with PRS seem to have a significantly higher need for VPI surgery than CP-only patients. No significant difference in the rate of VPI surgery was found when syndromic PRS patients were compared with nonsyndromic. Neither was there any significant difference between the rate of VPI surgery when different cleft types were compared or when the cleft palate had been repaired with a modified von Langenbeck versus a Sommerlad repair. We found no significant difference in the rate of syndromes between PRS patients with a CP and a control group of CP patients without PRS.

Filip et al., MULTIDISCIPLINARY ASPECTS OF PIERRE ROBIN SEQUENCE

Children and adolescents with PRS do not seem to be more at psychological risk than CP children without PRS, unless the cleft is associated with an additional condition with consequences for learning and/or development. The strong association between the presence of ASD in boys with PRS should be investigated in future research. Acknowledgment. The authors wish to thank Biostatistician Are Hugo Pripp Ph.D., Unit of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway, for his statistical advice.

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