Craniofacial dysostosis

Objectives: To examine the prevalence and nature of craniofacial abnormalities in patients with Marfan's syndrome and to investigate the relationship between craniofacial abnormalities and obstructive sleep apnea (OSA) severity in these patients.

Design: Cross-sectional.

Setting: Marfan's syndrome clinic in a tertiary teaching hospital.

Patients: Fifteen consecutive adult patients (7 men and 8 women; mean [[+ or -] SD] age, 34.8 [+ or -] 13.2 years) who had Marfan's syndrome.

Measurements and results: Apneic status was determined from standard overnight polysomnography testing. Measurements from standardized lateral cephalometric radiographs were compared to normative data. Thirteen patients had OSA, which was defined as an apnea/hypopnea index (AHI) of > 5 episodes per hour (mean AHI, 22 [+ or -] 15 episodes per hour). A high prevalence of craniofacial abnormalities was found with significant gender differences for some of the variables. Significant abnormalities for the entire group were bimaxillary retrusion, a reduced maxillary length, an increased total anterior face height, a long lower anterior face height, an obtuse gonial angle, a steep mandibular plane, a reduced posterior nasal airway height, a reduced posterior airway space, and an increased distance from the mandibular plane to the hyoid bone. Univariate analysis revealed significant correlations among the total anterior face height, the upper anterior and posterior face heights, the mandibular length, and AHI. There was a significant correlation between the rank of the number of cephalometric abnormalities per patient and AHI in those patients with OSA.

Conclusions: Craniofacial abnormalities are common in patients with Marfan's syndrome. The relationship between some cephalometric parameters and apnea severity suggests a potential role of craniofacial structure in the pathogenesis of OSA in these patients. (CHEST 2001; 120:1455-1460)

Key words: craniofacial abnormalities; Marfan's syndrome; obstructive sleep apnea

Abbreviations: AHI = apnea/hypopnea index; ANB = angle from the deepest midline point on the maxillary alveolus between the anterior nasal spine and the maxillary alveolar crest to the deepest midline point on the maxillary alveolus between the mandibular alveolar crest and the pogonion; ANS = anterior nasal spine. BMI = body mass index. CMP-H = distance from the mandibular plane to the hyoid bone; Co = condylion; Co-A = slightly reduced distance from the condylion to the deepest midline point on the maxillary alveolus between the anterior nasal spine and the maxillary alveolar crest; Co-Gn = distance from the Co to the Gn (mandibular length); Co-Go-Me = angle between the condylion and the gonion and the gonion and the menton; Go = gonion; LAFH = lower anterior face height; Me = menton; MP-H = distance from the mandibular plane to the hyoid bone; N = nasion; OSA = obstructive sleep apnea; PAS = posterior airway space; PNS = posterior nasal spine; PNS-P = the distance from the posterior nasal spine to the tip of the uvula; point A = the deepest midline point on the maxillary alveolus between the anterior nasal spine and maxillary alveolar crest; point B = the deepest midline point between the mandibular alveolar crest and the pogonion; S = sella; Sa[O.sub.2]min = minimum oxygen saturation; SE-PNS = distance from the sphenoidale to the posterior nasal spine; S-N = distance from the sella to the nasion; SNA = angle from sella to nasion to the subspinale point; SNB = reduced angle from the sella to the nasion to the supramentale point; TAFH = total anterior face height; UAFH = upper anterior face height; UPFH = upper posterior face height

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Marfan's syndrome is inherited as an autosomal-dominant trait and is associated predominantly with abnormalities of the following three major connective tissue systems: the musculoskeletal; the cardiovascular; and the ocular. (1-3) More recently, the involvement of the skin, the CNS, and the lungs has been reported. (3) The diagnosis is based on clinical criteria and family history. (4) The cause has been attributed to mutations in FBN1, the gene that encodes fibrillin-1. (4) The prevalence of Marfan's syndrome is estimated to be approximately I case per 10,000 persons in the general population. The life expectancy of patients with Marfan's syndrome is greatly reduced, mainly due to aortic complications. (5)

A high prevalence of obstructive sleep apnea (OSA) syndrome among patients with Marfan's syndrome has been reported. (6) OSA is a common disorder that is characterized by repetitive obstruction of the upper airway during sleep. The typical patient with OSA is middle-aged, centrally obese, and male. (7) In marked contrast, patients with Marfan's syndrome are tall, thin, and generally young. The reason for the high prevalence of OSA in these patients is uncertain. Increased upper airway collapsibility during sleep has been shown in this group, and it has been postulated that this relates to the known connective tissue defect of the syndrome. (8) Furthermore, high nasal airway resistance has been reported in patients with Marfan's syndrome, and this appears to be mediated by the characteristic maxillary constriction and high arched palate that is associated with the syndrome. (9,10) Marfan's syndrome, like many other congenital syndromes, is associated with various craniofacial abnormalities. Numerous studies have suggested an important role of craniofacial abnormalities in the development of OSA, especially among thin patients. (11) Hence, an important possibility is that the craniofacial abnormalities associated with Marfan's syndrome result in a predisposition to OSA in these patients. However, there has been little systematic evaluation of the craniofacial skeleton in these patients to date. Therefore, the aims of this study were to examine the prevalence and nature of craniofacial abnormalities in patients with Marfan's syndrome and to investigate the relationship between craniofacial abnormalities and the severity of OSA.

MATERIALS AND METHODS

Patients

Fifteen consecutive adult patients (7 men and 8 women) with Marfan's syndrome presenting for routine follow-up at a specialist Marfan's syndrome clinic of a university teaching hospital were studied. All patients fulfilled the diagnostic criteria for Marfan's syndrome. (4) Informed consent was obtained from all patients, and the study was approved by the ethics committee of our institution.

Sleep Studies

All of the patients underwent standard nocturnal polysomnography testing, as previously described. (6) Sleep recordings were scored in 30-s epochs and were staged according to standard criteria. (12) Calculated respiratory variables were apnea/hypopnea index (AHI; ie, the number of apneas and hypopneas per hour of sleep), and minimum oxygen saturation (Sa[O.sub.2]min). Airflow was measured using nasal prongs attached to a pressure transducer. Apnea was defined as a cessation of airflow for at least 10 s with oxygen desaturation of > 4% and/or association with arousal. Hypopnea was defined as a reduction in amplitude of airflow or thoracoabdominal wall movement of > 50% of the baseline measurement for > 10 s with an accompanying oxygen desaturation of at least 4% and/or association with arousal. These respiratory events were defined as obstructive if they occurred in association with continued diaphragmatic electromyographic activity and thoracoabdominal wall movement.

Cephalometry

Lateral cephalometric radiographs were taken using a standardized technique. (13) The subject was in the sitting position with the Frankfort plane horizontal and the teeth in centric occlusion. The distance from the mid-sagittal plane to the film was standardized to 15 cm. The distance from the source to the midsagittal plane was fixed at 152 cm. This produced a magnification of 1.1. The cephalogram was taken at end-inspiration and without swallowing. All radiographs were traced and interpreted by an experienced orthodontist who had no knowledge of the patients' clinical characteristics. Linear and angular measurements were made from each tracing. The magnification factor was taken into account to adjust all the linear measurements to natural size. The reference landmarks and the lines used in the analysis are shown in Figure 1. The data were compared to population norms from Bhatia and Leighton. (14) Normative data for the posterior airway space (PAS), the distance from the mandibular plane to the hyoid bone (MP-H), and the length of the soft palate (ie, the distance from the posterior nasal spine to the tip of the uvula [PNS-P]) were from Guilleminault et al, (15) and data for the posterior nasal airway height (ie, the distance from the sphenoidale to the posterior nasal spine [SE-PNS]) were from deBerry-Borowiecki et al. (16) The limits of normality were conservatively defined as the 5th and 95th percentiles, using published normal values for the various measurements.

[FIGURE 1 OMITTED]

Statistical Analysis

Statistical comparisons between patients and normative data were carried out by calculating the Z score (ie, Z = [patient mean -- normal mean]/SE of the difference between the means). The statistical significance of the Z score was determined from statistical tables for appropriate degrees of freedom. Statistical comparisons of anthropometric and polysomnographic variables between male and female patients were carried out by unpaired t tests. The Mann-Whitney U test was used to make comparisons if the data were not normally distributed. Univariate regression analysis was used to determine which cephalometric variables correlated with the degree of OSA, as reflected by the AHI and Sa[O.sub.2]min. Spearman's rank correlation (r) was calculated to examine the relationship between the rank of the number of cephalometric abnormalities per patient and the AHI. Multiple linear regression was used to determine which combination of cephalometric measurements correlated with Sa[O.sub.2]min. A p value < 0.05 was considered to be statistically significant. Descriptive statistics are presented as the mean [+ or -] SD. Estimated means are presented as the mean [+ or -] SEM.

RESULTS

All patients were white and had the typical clinical features of Marfan's syndrome (ie, they were generally young, tall, and thin; Table 1). Men were significantly taller than women (188 [+ or -] 3 vs 175 [+ or -] 2 em; p < 0.01) and had a greater neck circumference (37.0 [+ or -] 1.0 vs 34.0 [+ or -] 0.5 cm; p < 0.05). Thirteen of the 15 patients had OSA, which was defined as an AHI more than five episodes per hour. The severity of apnea in these patients was mild to moderate, with a mean AHI of 22 [+ or -] 15 episodes per hour and a mean Sa[O.sub.2]min of 86 [+ or -] 7%. Nine patients had an AHI of > 10 episodes per hour, and five patients had an AHI of > 20 episodes per hour. Men had more severe OSA than the women (mean AHI, 32 [+ or -] 5 vs 9 [+ or -] 1 episodes per hour, respectively; p < 0.01; and mean Sa[O.sub.2]min, 83 [+ or -] 3% vs 91 [+ or -] 1%, respectively; p < 0.05).

Many of the cephalometric measurements were found to be abnormal in the group as a whole compared to published normative data (Table 2). The patients were found to have a mean of 8 of the 22 cephalometric variables outside the limits of normality, with a range of 4 to 13 abnormalities per patient. The predominant abnormalities for the entire group were as follows: retrusion of the maxilla and mandible (ie, a reduced angle from the sella [S] to the nasion [N] to the subspinale point [SNA] and a reduced angle from the S to the N to the supramentale point [SNB] with a normal angle from the deepest midline point on the maxillary alveolus between the anterior nasal spine [ANS] and the maxillary alveolar crest [point A] to the deepest midline point on the maxillary alveolus between the mandibular alveolar crest and the pogonion [point B] [ANB]); an increased angle from the mandibular plane to the anterior cranial base; an increased angle between the condylion [Co] to the gonion [Go] and the Go to the menton [Me] [ie, the gonial angle or Co-Go-Me]; a reduced SE-PNS; a slightly reduced distance from the Co to point A [Co-A], called the maxillary length; an increased MP-H; a reduced PAS; an increased total anterior face height [TAFH]; and an increased lower anterior face height [LAFH]). Men were found to have significant reductions in SNA (70.6 [+ or -] 1.5 vs 82.0 [+ or -] 0.9 mm; p < 0.0005) and SNB (70.0 [+ or -] 1.0 vs 79.7 [+ or -] 0.9 mm; p < 0.0001) with a normal ANB. They also had a significantly reduced Co-A (83.7 [+ or -] 1.4 vs 88.4 [+ or -] 0.8 mm; p < 0.01) and a significantly increased distance from the S to the N (S-N) (74.1 [+ or -] 1.1 vs 71.5 [+ or -] 0.6 mm; p < 0.05). Women had an increased TAFH (118.6 [+ or -] 1.9 vs 111.9 [+ or -] 1.1 mm; p < 0.01).

Univariate regression analysis revealed an association between some cephalometric measurements and apnea severity as measured by AHI (Table 3). There was also a significant correlation between PAS and Sa[O.sub.2]min (r = 0.65; p < 0.01), but not with AHI. In the 13 patients with OSA, there was a significant relationship between the rank of the number of cephalometric abnormalities per patient and AHI (r = 0.65; p < 0.05). However, the two patients without OSA also had a significant number of abnormalities (seven in one patient and eight in the other), but the PAS was significantly greater in these individuals than in those with OSA (15.0 [+ or -] 1.0 vs 9.3 [+ or -] 0.9 mm; p < 0.05). Multiple linear regression revealed that PAS and MP-H were both independent predictors of Sa[O.sub.2]min, and together they explained 67% of the variance in Sa[O.sub.2]min ([R.sup.2] = 0.67; p < 0.005). Neither of these variables was a significant predictor of AHI. Body mass index (BMI) was not an independent predictor of either AHI or Sa[O.sub.2]min in these patients.

DISCUSSION

This cephalometric study of patients with Marfan's syndrome provides evidence that such patients have a high prevalence of craniofacial abnormalities. The finding of a relationship between indexes of apnea severity and various cephalometric measurements suggests that these structural abnormalities are likely to play a role in predisposing these individuals to OSA.

Various craniofacial abnormalities have been described in patients with Marfan's syndrome, although the literature on this topic has consisted predominantly of case reports. Reported abnormalities include dolichocephaly, maxillary constriction with a high arched palate, maxillary and mandibular retrognathia, prognathia, and macrocephaly. (17-22) To our knowledge, the current study is the first to examine airway measurements in addition to conventional orthodontic measurements from cephalometric radiographs in patients with Marfan's syndrome and has confirmed the high prevalence of abnormalities in these patients. All of the patients had at least four of the assessed variables outside the limits of normality. In keeping with other clinical aspects of this syndrome, there was a degree of heterogeneity in the types and degrees of abnormalities that were identified. In the total group, the significant abnormalities were maxillary and mandibular retrusion with mandibular growth predominantly vertical, a reduced maxillary length, an increased total anterior face height, a long LAFH, an obtuse gonial angle, a steep mandibular plane, a reduced posterior nasal airway height, a reduced PAS, and an increased MP-H. Some of these findings are in accordance with those previously described.

The observed cephalometric abnormalities are similar to those reported in the general OSA population. (11) Several studies have found that various measurements correlate with the degree of OSA, suggesting that structural abnormalities may play a role in its pathophysiology. An increased MP-H (23,24) and a decreased PAS (23) have been shown to be significant predictors of apnea frequency. Davies and Stradling (25) reported significant correlations between the oxygen saturation dip rate and hyoid position, soft palate length, and angle of the hard palate to the spine. Using stepwise linear regression analysis, they found that neck circumference and retroglossal space were the only significant independent correlates. Similarly, apnea frequency has been found to correlate with the logarithm of tongue volume, the position of the mandible (SNB), the maxilla/mandible relationship (ANB), the overbite, and BMI in a stepwise regression analysis. (26) In the present study, a univariate analysis revealed significant correlations among the TAFH, the upper anterior face height (UAFH), the upper posterior face height (UPFH), mandibular length (Co-Gn), and the AHI. Furthermore, there was a significant correlation between the rank of the number of cephalometric abnormalities per patient and AHI in the 13 patients with OSA. Similarly, multiple linear regression revealed that MP-H and PAS explained 67% of the variability in Sa[O.sub.2]min levels, but they were not independent predictors of AHI. The reduced PAS may be an explanation for the increased prevalence of OSA in patients with Marfan's syndrome since the two Marfan's syndrome patients without OSA had a normal or increased PAS. Notably, BMI was not found to be a predictor of apnea severity in these tall, thin individuals. This is consistent with a proposed model of OSA in which the degree of craniofacial abnormality in a patient determines the degree of obesity required to cause OSA. (27,28) Hence, at one end of the spectrum are patients who are thin but have a significant degree of craniofacial abnormality, such as in Marfan's syndrome, and at the other end are obese individuals without significant craniofacial abnormality.

The cause of the craniofacial abnormalities observed in patients with Marfan's syndrome is not yet clear. In particular, it is not clear whether they are the direct result of the genetic abnormality or whether environmental influences play a role. The patterns of abnormalities observed in this study are known to be associated with chronic airway obstruction during childhood development and are collectively termed "long face syndrome" in the orthodontic literature. (20-31) Oral breathing consequent to nasal obstruction has been implicated to cause modification of head posture, which may influence facial development and dentofacial growth. (30) Animal studies further support the important role of airway patency on facial development. (32) Hence, it is possible that the craniofacial abnormalities observed in patients with Marfan's syndrome are the result of chronic airway obstruction, which is associated with mouth breathing. This is supported by the observation that these patients have high nasal resistance, (9) which appears to be causally related to the characteristic maxillary constriction and high-arched palate. (10) Moreover, this may have therapeutic implications that are particularly relevant to Marfan's syndrome, since expansion of a narrow maxilla may improve nasal resistance (33) and sleep-disordered breathing. (34)

Our study has some potential limitations. We did not study concurrent control subjects who were tall and thin but did not have Marfan's syndrome. The normative data we used from Bhatia and Leighton (14) are those of 20-year-old white subjects. There is little significant change in the dentofacial complex after this age, and therefore it is reasonable to use these data for adults. The data for the two 16-year-old patients were compared to appropriate age-matched data. Nevertheless, it will be necessary to study a group of tall, thin control subjects (with and without airway obstruction) to determine whether the abnormalities identified in this study are in fact specifically related to Marfan's syndrome or whether they are related to other factors (eg, tall stature or airway obstruction). The sample size was small, and therefore it is possible that with a larger group greater heterogeneity in structural abnormalities may have been detected.

In conclusion, this study has demonstrated a high prevalence of craniofacial abnormalities in patients with Marfan's syndrome. Coupled with the finding that some of these variables correlated with apnea severity, these data suggest that craniofacial abnormalities play a potential role in the development of OSA in these patients who are tall and thin, in contrast to the typical OSA population.

ACKNOWLEDGMENTS: The authors gratefully acknowledge the assistance of the staff of the Sleep Disorders Center and Dr. Richmond Jeremy from the Marfan Clinic at Royal Prince Alfred Hospital. We thank Dr. Anthony Pistolese for his analysis of the cephalometric radiographs.

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* From the Sleep Disorders Center (Drs. Cistulli and Gotsopoulos), Department of Respiratory Medicine, St George Hospital, University of New South Wales, Sydney, Australia; and the Sleep Disorders Center (Dr. Sullivan), Royal Prince Alfred Hospital, University of Sydney, Australia.

Supported by a National Health and Medical Research Council of Australia Scholarship and the Australian Lung Foundation/ Sensormedics Fellowship in Sleep Disorders (PAC).

Manuscript received November 22, 2000; revision accepted May 1, 2001,

Correspondence to: Peter A. Cistulli, MBBS, PhD, FCCP, Sleep Disorders Center, Department of Respiratory Medicine, St George Hospital, Gray St, Kogarah 2217, NSW, Australia; e-mail: e-mail: p.cistulli@unsw.edu.au

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