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Extracraniofacial anomalies in craniofacial microsomia: retrospective analysis of 991 patients

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Craniofacial microsomia (CFM) is characterized by unilateral or bilateral underdevelopment of the facial structures arising from the first and second pharyngeal arches, but extracraniofacial anomalies may also be present. This retrospective study provides an overview of the prevalence, types, and characteristics of extracraniofacial anomalies in patients with CFM. All patients diagnosed with CFM seen at four craniofacial centres were included. The patient charts were reviewed and data on patient characteristics and extracraniofacial anomalies were extracted. Of the 991 patients included, 462 (47%) had extracraniofacial anomalies. The prevalence of extracraniofacial anomalies in the various tracts was as follows: vertebral 28%, central nervous system 11%, circulatory system 21%, respiratory tract 3%, gastrointestinal tract 9%, and urogenital tract 11%. Compared to patients without extracraniofacial anomalies, those with an extracraniofacial anomaly were at higher risk of having additional extracraniofacial anomalies in other tracts. The prevalence of extracraniofacial anomalies was greater in patients with bilateral CFM, a more severe mandibular deformity, or facial nerve or soft tissue deformity. Patients with CFM should be screened for extracraniofacial anomalies by physical examination with specific attention to the circulatory, renal, and neurological tracts. Diagnostically, electrocardiography, echocardiography, spine radiography, and renal ultrasound should be performed for patients at risk of extracraniofacial anomalies.
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EXTRACRANIOFACIAL ANOMALIES IN CRANIOFACIAL MICROSOMIA:
RETROSPECTIVE ANALYSIS OF 991 PATIENTS
Short running title: Extracraniofacial anomalies in CFM
Ruben W. Renkema, BSca ; Cornelia J.J.M. Caron, MD, DMDa ; E. Pauws, BSc, PhDb, Eppo B.
Wolvius, DMD, MD, PhDa ; Jan Aart M. Schipper, BSca ; Wietse Rooijers, BSca ; David J. Dunaway,
FDS RSC FRCS (plast)c ; Christopher R. Forrest, MD, MSce ; Bonnie L. Padwa, MD, DMDd ; Maarten
J. Koudstaal, MD, DMD, PhDa,c,d
a The Dutch Craniofacial Center, Department of Oral and Maxillofacial Surgery, Erasmus
University Medical Center, Sophia’s Children’s Hospital Rotterdam
b UCL Great Ormond Street Hospital Institute of Child Health, London, UK
c The Craniofacial Unit, Great Ormond Street Hospital, London, United Kingdom
d Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, United States of
America
e Division of Plastic and Reconstructive Surgery, Department of Surgery, The Hospital for Sick
Children, Toronto, Canada
Head of Department: Professor Eppo B. Wolvius, DDS, MD, PhD
KEYWORDS
Craniofacial microsomia, oculo-auriculo-vertebral syndrome, Hemifacial Microsomia, Goldenhar,
extracraniofacial anomalies, extracranial anomalies, retrospective study.
ADDRESS OF CORRESPONDENCE:
Ruben W. Renkema, BSc
Department of Oral and Maxillofacial Surgery
Erasmus University Medical Center, Sophia’s Children’s Hospital Rotterdam
’s Gravendijkwal 230
3015 CE Rotterdam, The Netherlands
Phone: +31(0)107031277 / fax: +31(0)107033098
Email: r.renkema@erasmusmc.nl
FUNDING STATEMENT:
This study was not funded.
COMPETING INTERESTS STATEMENT:
There are no conflicts of interest in the materials or subject matter dealt with in the manuscript.
CONTRIBUTORSHIP STATEMENT:
All authors made substantial contributions to conception and design, acquisition of data, or
analysis and interpretation of data. All authors were involved in drafting the article or critically
revising it for important intellectual content. And, finally, all authors approved of the version to
be published.
ACKNOWLEDGEMENTS
-
ABSTRACT
Craniofacial microsomia (CFM) is characterized by a unilateral or bilateral underdevelopment of
the facial structures arising from the first and second pharyngeal arches, but extracraniofacial
anomalies may be present. This retrospective study provides an overview of the prevalence and
types of extracraniofacial anomalies in patients with CFM and studied the characteristics of
patients with CFM and extracraniofacial anomalies. All patients diagnosed with CFM seen in four
craniofacial centers were included. Patients charts were reviewed and data on patient
characteristics and extracraniofacial anomalies were extracted. A total of 991 patients were
included. Forty-six percent of the patients had extracraniofacial anomalies. The prevalence of
extracraniofacial anomalies in all various tracts was: vertebral 28%, central nervous system 11%,
circulatory system 21%, respiratory tract 3%, gastro-intestinal tract 9%, and urogenital tract 11%.
Patients with an extracraniofacial anomaly had a higher risk for having additional
extracraniofacial anomalies in other tracts compared to patients without extracraniofacial
anomalies. The prevalence of extracraniofacial anomalies was greater in patients with bilateral
CFM, a more severe mandibular deformity or facial nerve or soft tissue deformity. Patients with
CFM should be screened for extracraniofacial anomalies by psychical examination with specific
attention aimed at the circulatory, renal, and neurological tracts. Diagnostically,
electrocardiography, echocardiogram, spine radiography and a renal ultrasound should be
obtained in patients at risk for extracraniofacial anomalies.
LEVEL OF EVIDENCE
Level III: Retrospective cohort study
INTRODUCTION
The first and second pharyngeal arches give rise to various facial structures such as the
mandible, maxilla, zygoma, ears, facial nerves and/or facial soft tissues (1). In patients with
craniofacial microsomia (CFM) the structures arising from these arches may be underdeveloped
or absent. The exact origin of this congenital disorder is yet unknown, although various theories
have been proposed. A disruption in the development of the first and second pharyngeal arches
during the first six weeks of development is potentially the cause of CFM (2-4). An error in
migration of neural crest cells has found to form craniofacial anomalies as found in patients with
CFM (5, 6). The clinical spectrum varies from a mild to severe phenotype and can be unilateral or
bilateral (3, 7, 8). Although the ears may be underdeveloped or absent, isolated microtia is
generally not regarded to be CFM (4).
Various classification systems have been proposed to categorize patients with CFM (6, 9-
14). The Pruzansky-Kaban classification is based on radiographic evaluation of the
underdevelopment of the mandible and temporomandibular joint, and is graded from mild to
severe in type I, -IIA, -IIB, or III (11, 15, 16). An alternative model, the O.M.E.N.S-plus
classification, focuses on the level of underdevelopment of the Orbit (O), Mandible (M), Ears (E),
Facial Nerve (N), Soft Tissue (S), and the presence of extracraniofacial anomalies (6, 9).
These extracraniofacial anomalies may be present in up to 55% of the patients with CFM
and may occur in the vertebral column and ribs, the central nervous system (CNS), the circulatory-
, respiratory-, gastro-intestinal-, and/or urogenital tract (6, 17-19). According to previous
literature, the prevalence of extracraniofacial anomalies in CFM varies from 2% to 79% (6, 17,
19). Patients with a higher O.M.E.N.S. score are thought to have increased incidence of
extracraniofacial anomalies (6). Additionally, patients with an extracraniofacial anomaly have a
higher incidence of additional extracraniofacial anomalies in other tracts (18, 20). To recognize
and potentially treat these anomalies in an early state, clinicians should be aware of the potential
extracraniofacial anomalies in CFM. However, no literature is available on which patients with
CFM are at an increased risk of having extracraniofacial anomalies and should be screened for
these anomalies.
The aim of this study is to provide an overview of the extracraniofacial anomalies found
in CFM and to determine which patients with CFM have an increased likelihood of having
extracraniofacial anomalies.
METHODS
Subjects and Data collection
A global multicenter retrospective study was initiated at the craniofacial centers of
Erasmus University Medical Center (EMC), Rotterdam, The Netherlands; Great Ormond Street
Hospital (GOSH), London, United Kingdom; Boston Children’s Hospital (BCH), Boston, United
States of America, and The Hospital for Sick Children, Toronto, Canada. This study was approved
by the Institutional Review Boards (Rotterdam: MEC-2012-248; London: 14DS25; Boston: X05-
08-058; Toronto: 1000053298).
All patients diagnosed with CFM seen in these craniofacial centers were included for
further analyses. Since CFM is a clinical diagnosis, patients with clinical and/or radiographic
images, i.e. panoramic x-rays and/or CT head, were included in this study. Patients in which the
diagnosis of CFM could not be confirmed with the use of clinical and/or radiographic imaging and
patients with isolated microtia were excluded. Patient charts of all included patients were
reviewed and data on age, sex, affected side, Pruzansky-Kaban classification, O.M.E.N.S.
classification and the presence of extracraniofacial anomalies was extracted. Patients with
extracraniofacial anomalies were further analyzed. For each extracraniofacial anomaly present,
data on type, location and date of diagnosis of the anomaly were noted.
The O.M.E.N.S classification system was used to grade the facial malformations in CFM
patients (9, 21). The severity of the mandibular hypoplasia was determined by using the
Pruzansky classification modified by Kaban et al. (11, 15, 16). In patients with bilateral CFM both
facial- and mandibular sides were scored, but only the scores of the most affected side of the
face were used for analysis. In this study, the M-score of the O.M.E.N.S. score was based on the
Pruzansky-Kaban classification scored on radiography as proposed by Vento et al.(9) and not on
clinical photography as suggested in the PAT-CFM developed by Birgfeld et al (21).
Statistical analysis
Statistical analyses were performed using SPSS version 20.0 for Windows (2011, SPSS Inc.,
Chicago, IL, USA). Descriptive statistics were used. Equality of groups was tested with the
Pearson's Chi-square Test for Independence. Fisher’s Exact Test was used when the assumptions
for Pearson-Chi square test were violated (i.e. expected count less than 10). A univariate binary
logistic regression model was used to evaluate the association between the extracraniofacial
anomalies, and between the O.M.E.N.S and Pruzansky score. A P-value of <.05 was considered to
be statistically significant.
RESULTS
Characteristics of patient population
A total of 1132 patients with CFM were diagnosed between all four craniofacial centers.
Following exclusion of 141 patients due to diagnostic inconclusiveness or isolated microtia, 991
patients were included for further analyses. Fifty-five percent (n=527) was male and 47% (n=464)
was female. Most patients had unilateral CFM (n=827), 177 had bilateral CFM and in 47 the
affected side was unknown. Patient characteristics are shown in table 1.
Characteristics of patients with extracraniofacial anomalies
Of the 991 patients included in this study, 46 % (n=462) of patients were diagnosed with
at least one extracraniofacial anomaly. The number of extracraniofacial anomalies per patient
varied and could by present in various tracts simultaneously, as shown in figure 1. Fifty-five
percent of the patients with an extracraniofacial anomaly was male (n=252) and forty-five
percent was female (n=210). Seventy-nine percent (n=367) of the patients with an
extracraniofacial anomaly had unilateral CFM, 17 % (n=79) had bilateral CFM and of 4% (n=16)
of the patients with an extracraniofacial anomaly the affected side was unknown. The
prevalence of extracraniofacial anomalies was found to be significantly higher in patients with
bilateral CFM than in patients with unilateral CFM (Pearson’s χ2 (df 1)=22.03, Odds ratio=2.61,
95% CI 1,7-3,9, P-value=<0.0001).
Types of extracraniofacial anomalies
The various types of extracraniofacial anomalies diagnosed in our study population are
shown in table 2. Vertebral anomalies were most frequently seen, in 28% of the patients with
CFM (n=275). Most seen anomalies were scoliosis, block vertebrae, hemivertebrae, and
anomalies of the ribs. Anomalies of the central nervous system were reported in 11% of the
patients with CFM (n=105). Hydrocephaly, ventriculomegaly, intracranial cysts, and Arnold Chiari
malformation were mostly seen. Of the 28 patients with anomalies of the spinal cord, such as
spina bifida or tethered cord, 27 patients had vertebral anomalies too (Odds ratio=77.84, P-
value=<0.001). Anomalies of the circulatory system were present in 21% of the patients with CFM
(n=205). Mostly seen were ventricular or atrial septal defects, patent ductus arteriosus, and
anomalies of the valves. Three percent of all patients with CFM (n=29) had an anomaly of the
respiratory tract (n=14), such as laryngo- or tracheomalacia, or lung hypoplasia. Of these 29
patients with a respiratory anomaly, 14 patients had a cardiac anomaly too. Anomalies of the
gastro-intestinal tract were present in 9% of the patients (n=89). Although the variety of
anomalies is large, inguinal hernia, imperforate anus, esophageal atresia, and umbilical hernia
were mostly seen. Urogenital anomalies occurred in 11% of the patients (n=108). Mainly, renal
aplasia, undescended testis, and hydronephrosis were observed.
Correlations extracraniofacial anomalies
Table 3. shows the statistical analysis of which patients with an extracraniofacial anomaly
had a higher incidence of additional extracraniofacial anomalies in other tracts. Patients with an
extracraniofacial anomaly in any tract were found to have a significant higher risk for additional
extracraniofacial anomalies in other tracts, except for anomalies of the respiratory tract. The
correlation strength for the presence of extracraniofacial anomalies in different tracts varied
from a Pearson’s χ2 (df 1) of 88.72 and an odds ratio of 6.64 (p=<0.001) for vertebral anomalies
and anomalies of the central nervous system, to a Pearson’s χ2 (df 1) of 15.53 and an odds ratio
of 2.33 (p=<0.001) for circulatory anomalies and anomalies of the urogenital tract. Anomalies of
the respiratory tract were observed in fewer patients than anomalies of other tracts and were
positively correlated with the presence of anomalies of the circulatory system (Odds ratio=3.77,
P-value=0.001) and gastro-intestinal tract (Odds ratio=4.96, P-value=0.001).
The O.M.E.N.S. score was used to examine a possible correlation between the facial
malformations in CFM and the presence of extracraniofacial anomalies. Of various patients, data
of components of the O.M.E.N.S. score was missing: in 217 patients the Orbit score was unknown,
in 328 patients the Mandible score was unknown, the Ear score was unknown in 242 patients, in
598 patients the Nerve score were not available, and the Soft Tissue score was unknown in 233
patients.
The statistical analysis of the correlation of the O.M.E.N.S. score with extracraniofacial
anomalies is displayed in table 4. A higher incidence of extracraniofacial anomalies was observed
in patients with a higher Mandible score, Nerve scores, or Soft Tissue score of the O.M.E.N.S.
score. This significant correlation was not observed in patients with a higher Orbit or Ear score.
A positive correlation between the Orbit score and extracraniofacial anomalies was solely
present for vertebral anomalies and not for extracraniofacial anomalies in other tracts. The Ear
score was positively correlated with circulatory anomalies and not with extracraniofacial
anomalies in other tracts. The mandible score had the highest correlation strength for the
presence of extracraniofacial anomalies compared to other components of the O.M.E.N.S. score
(Pearson’s r=0.331, Odds ratio=1.39, P-value=<0.001).
DISCUSSION
The aim of this study was to present an overview of the extracraniofacial anomalies in
CFM and to determine which patients with CFM have an increased likelihood for having these
anomalies. A total of 991 patients were included, with a male to female ratio of 1.14:1, which is
in line with previous literature (22). Eighteen percent of the patients were diagnosed with
bilateral CFM, which is higher than the 13,6% reported by meta-analysis by Xu et al (22).
Forty-six percent of all patients studied (n=462) were diagnosed with extracraniofacial
anomalies. The extracraniofacial anomalies were observed in all various tracts, such as the
vertebral column (in 28%), central nervous system (in 11%), circulatory (in 21%), gastro-intestinal
(in 9%), and urogenital (in 11%) tract, but were considerably scarce in the respiratory tract (in
3%). This may be due to a difference in the embryological development of these organs. The
etiology of CFM is unknown, yet various theories have been proposed (2-4). Hereditary cases of
CFM are known and when examining family members of patients with CFM with more detail for
dysmorphologies, 45% of the family members tend to have some manifestation that could be
part of CFM (23). Various genes have been proposed to cause CFM, but no single origin has been
identified (4, 20). However, a recent genome-wide association study has identified a number of
genetic loci associated with CFM that express neural crest genes (24). An alteration in the
development of the first and second pharyngeal arches during the first six weeks of development
appears to be the cause of CFM (3, 4). During these weeks the facial structures are formed by the
first and second pharyngeal arches after neural crest cells migrated into these arches forming
ectomesenchyme (25-27). A defect in the generation or migration of neural crest cells has been
suggested to be the origin of the developmental deformities found in CFM (25-27). Abnormal
migration of neural crest cells has been found to form the basis of craniofacial, vertebral, central
nervous system, cardiovascular, and urogenital anomalies (5, 6, 28). The lungs are formed out of
the primitive foregut and are further developed by epithelia, which is of endodermal descent,
and mesenchymal cells (29). During development of the lung, neural crest cells play a role in the
development of the intrinsic neurons which innervate the airway smooth muscles (30).
Disturbing this process may originate in inadequate formation of the lungs. Although neural crest
cells play a role in the development of the respiratory tract, less evidence is available on a link
between neural crest cells and anomalies in this tract. This may be the reason why less anomalies
of the respiratory tract were found in our studied cohort compared to anomalies in other tracts.
The prevalence of extracraniofacial anomalies in CFM in our studied cohort is 46%, which
is considerably higher than the incidence of 0,001%-2% in live births in the healthy population
(31-33). The prevalence found in our studied population is similar to the 44% found by Rollnick
et al. (19), but lower than the 55% reported by Horgan et al. (6) and the 69% by Barisic et al (17).
This may be due to differences in patient selection, study characteristics and sample size. In the
study by Rollnick et al. (n=294) 31% of the included patients had isolated microtia, which may
have led to a lower prevalence of extracraniofacial anomalies in their studied population since
these patients do not fit the criteria of CFM used in this study (19). The study by Horgan et al.
(n=121) included patients with “hemifacial microsomia without further specification of the
clinical criteria used (6). Barisic et al. (n=269) included patients with microtia/ear anomalies and
at least one major anomaly of the oculo-auriculo-vertebral spectrum (17). The prevalence of
extracraniofacial anomalies found in our study may be higher since our study is retrospective and
data are based on chart review. Thereby, not all extracraniofacial anomalies lead to clinical
symptoms and may therefore remain undiagnosed. Although the actual prevalence remains
uncertain, this large retrospective study shows extracraniofacial anomalies are common in CFM.
Only a well-designed prospective study could comprehensively characterize extracraniofacial
anomalies in CFM.
Horgan et al. found, by using the sum of the O.M.E.N.S. score, that patients with a higher
O.M.E.N.S. score had a higher risk for extracraniofacial anomalies (6). In our studied cohort,
patients with bilateral CFM, a higher Pruzanksy-Kaban score, and/or a higher Nerve, and/or Soft
Tissue score on the O.M.E.N.S. scale had a significant higher incidence of extracraniofacial
anomalies. Caron et al. and Tuin et al. found that deformities of the Orbit, Mandible, and Soft
Tissue, which originate from the first pharyngeal arch, are significantly correlated with each other
(18, 34). A correlation between the structures derived from the second pharyngeal arch as scored
in the Nerve and Ear score, and the Nerve and Soft Tissue score was also found (34). This study
did not find a correlation between the presence of extracraniofacial anomalies and the
O.M.E.N.S. score clusters as described by Caron et al. and Tuin et al. This could be due to a
different, systemic pathophysiological mechanism compared to patients with isolated facial
anomalies.
Patients with an extracraniofacial anomaly had a significant higher risk for additional
extracraniofacial anomalies in other tracts compared to patients without extracraniofacial
anomalies. This correlation was present in all various tracts these anomalies can occur in, except
for the respiratory tract and vertebrae, and the respiratory tract and central nervous system.
Tasse et al. found a significant correlation between genito-urinary anomalies and vertebral
anomalies, but anomalies of the brain were not correlated with the presence other
extracraniofacial anomalies in their studied cohort (10). The significant correlation between
anomalies of the circulatory system and respiratory tract was also observed by Kumar et al. (35)
but not by Barisic et al (17). Both studies did not observe a significant correlation between
anomalies of the circulatory system and urogenital tract, as found in our study (17, 35).
Since our study is retrospective, it is uncertain whether patients with an extracraniofacial
anomaly were assessed in more detail for the presence of additional anomalies. Therefore, a
detection bias may be present. Nevertheless, this study shows that extracraniofacial anomalies
are common in patients with CFM. Patients with CFM should be screened for potential harmful
anomalies. Therefore, thorough physical examination should be performed in all patients with
CFM. Anomalies of the circulatory system should be ruled out by cardiac evaluation using
electrocardiography and/or echocardiogram in patients with a higher risk for extracraniofacial
anomalies (33, 36). A renal ultrasound to diagnose urogenital anomalies in an early stage should
be obtained in these patients as well (37). Neurological evaluation should be performed and if
abnormal, an MRI of the brain and spine should be performed to rule out any anomalies (38, 39).
If vertebral anomalies are suspected, standard upright posterior-anterior and lateral radiographs
should be obtained (38, 40).
CONCLUSION
The prevalence of extracraniofacial anomalies in CFM in our studied cohort of 991
patients was 46%. Patients with bilateral CFM, and/or a high Pruzansky-Kaban score, or a high
Nerve and/or Soft Tissue on the O.M.E.N.S. scale have a higher risk for extracraniofacial
anomalies. Having extracraniofacial anomalies increases the risk for having additional
extracraniofacial anomalies. All patients with CFM should be screened for extracraniofacial
anomalies by a thorough physical examination with specific attention aimed at the circulatory,
renal, and neurological tracts. Additionally, electrocardiography, echocardiogram, spine
radiography and a renal ultrasound should be obtained in patients at risk for extracraniofacial
anomalies.
Regarding the pathogenesis of CFM, the abundance of extracraniofacial anomalies in CFM
patients and the strong correlation between them and with craniofacial (pharyngeal arch) defects
suggests that the basis for this disorder lies with the neural crest cells. The fact that the
pharyngeal arches are involved could be due to the fact the correct formation of these structures
relies heavily on correct migration of neural crest cells during early embryonic development.
Table 1. Demographics for patients with and without extracraniofacial anomalies
Extracraniofacial anomalies
Yes
No
Total
Total
462
529
991
(100%)
Sex
Male
252
275
527
(53%)
Female
210
254
464
(47%)
Laterality
Unilateral
367
460
827
(83%)
Bilateral
79
38
117
(12%)
Unknown
16
31
47
(5%)
Affected side
(UCFM)#
Right
199
264
463
(56%)
Left
168
196
364
(44%)
Orbit*
0
183
227
410
(53%)
1
69
60
129
(17%)
2
53
50
103
(13%)
3
41
53
94
(12%)
4
24
14
38
(5%)
Mandible**
0
0
1
1
(1%)
1
63
98
161
(24%)
2A
72
100
172
(26%)
2B
89
86
175
(26%)
3
97
57
154
(23%)
Ear*
0
45
69
114
(15%)
1
51
60
111
(15%)
2
56
39
95
(13%)
3
193
214
407
(54%)
4
14
8
22
(3%)
Nerve*
0
100
126
226
(57%)
1
21
25
46
(12%)
2
39
27
66
(17%)
3
24
11
35
(9%)
4
11
9
20
(5%)
Soft Tissue*
0
55
65
120
(16%)
1
132
193
325
(43%)
2
127
116
243
(32%)
3
47
23
70
(9%)
UCFM = unilateral craniofacial microsomia ; #In unilateral cases of craniofacial microsomia ;
*Orbit, Ear, Nerve, Soft Tissue score on the O.M.E.N.S. scale ; **Mandible score based on
Pruzansky-Kaban classification ; ^See Table 4. for statistical analysis
Figure 1. Percentage of patients with extracraniofacial anomalies in multiple tracts
Not present
53%
In one tract
24%
In two tracts
13%
In three tracts
7%
In four tracts
2%
In five tracts
1%
Table 2. Description of extracraniofacial anomalies
n.s.: not specified, *TAPVR: Total anomalous pulmonary venous return
Vertebral anomalies
(n=275)
Number patients
Central nervous system
anomalies
(n=105)
Number patients
Circulatory system
anomalies
(n=205)
Number patients
Respiratory tract
anomalies
(n=29)
Number patients
Gastro-intestinal tract
anomalies
(n=89)
Number patients
Urogenital tract
anomalies
(n=108)
Number patients
Scoliosis
162
Hydrocephaly
18
VSD
95
Laryngomalacia
15
Inguinal hernia
30
Renal aplasia
28
Block vertebrae
118
Ventriculomegaly
17
ASD
71
Lung hypoplasia
8
Imperforate anus
16
Undescended testis
15
Hemivertebrae
98
Intracranial cyst
17
Patent ductus
arteriosus
42
Tracheomalacia
7
Esophageal atresia
11
Hydronephrosis
14
Not specified
49
Arnold Chiari
12
Valve anomaly
22
Tracheal stenosis
2
Umbilical hernia
11
Renal ectopia
10
Ribs fusion
27
Microcephaly
11
Tetralogy of Fallot
16
Absence of tracheal
rings
1
Tracheoesophageal
fistula
8
Hypospadias
10
Butterfly vertebrae
25
Intracranial lipoma
11
Artery malformation
15
Not specified
1
Intestines anomaly
6
Phimosis
9
Ribs aplasia
25
Spina bifida occulta
10
Pulmonic valve
stenosis
13
Diaphragmatic hernia
5
Internal genital
anomalies
7
Ribs extra
23
Hypoplastic corpus
callosum
9
Arrhythmia
11
Meckel's diverticulum
4
Vesicoureteral reflux
6
Vertebral hypoplasia
18
Cerebral dysgenesis
9
Venous malformation
10
Intestinal malrotation
4
Bladder anomaly
6
Ribs hypoplasia
15
Not specified
8
Transposition of the
great arteries
10
Polysplenia
3
External genital
anomalies
6
Cervical ribs
12
Tethered cord
7
Ventricle anomaly
10
Diaphragm anomaly
3
Ureter anomaly
5
Lack of fusion
vertebrae
12
Cerebral
hemorrhage/infarction
8
Aortic anomaly
9
Liver anomaly
3
Hydrocele testis
5
Pectus deformity
12
Fatty filum terminale
5
TAPVR
6
Anal fistula
2
Renal hypoplasia
4
Cervical spine
instability
7
Meningocele
5
Dextrocardia
4
Omphalocele
2
Duplex kidney
anomalies
4
Rib anomaly n.s.
7
Cerebral hypoplasia
4
Situs inversus
1
Pyloric stenosis
2
Renal fusion
3
Occipitalization atlas
6
Encephalocele
4
Cardiomegaly
1
Situs ambiguous
1
Renal dysplasia
3
Atlanto-axial
subluxation
4
Syringomyelia
4
Mesocardia
1
Renal anomaly n.s.
3
Vertebral agenesis
3
Macrocephaly
4
Not specified
1
Sacralization
3
Intracranial mass n.s.
3
Os odontoideum
2
Absent septum
pellucidum
2
Extra vertebrae
2
Omo vertebral body
1
Table 3. Statistical analysis of the extracraniofacial anomalies in the various tracts
Extracraniofacial anomalies (number of patients)
CNS
(n = 105)
Circulatory
(n = 205)
Respiratory
(n = 29)
GI#
(n = 89)
Urogenital
(n = 108)
Extracraniofacial anomalies (number of patients)
Vertebral
(n = 275)
88.72
49.36
*
36.37
37.87
Pearson’s χ2
6.64
3.01
2.17
3.67
3.41
Odds ratio
0.30
0.22
-
0.19
0.20
Phi coefficient
4.30-10.26
2.23-4.23
0.99-1.06
2.35-5.71
2.27-5.13
95% CI
<0.0001
<0.0001
0.055
<0.0001
<0.0001
P-value
CNS
(n = 105)
-
24.13
*
*
17.30
Pearson’s χ2
2.82
0.62
3.49
2.83
Odds ratio
0.16
-
-
0.13
Phi coefficient
1.84-4.32
0.15-2.64
2.06-5.90
1.70-4.70
95% CI
<0.0001
0.76
<0.0001
<0.0001
P-value
Circulatory
(n = 205)
-
-
*
41.87
15.53
Pearson’s χ2
3.77
4.05
2.33
Odds ratio
-
0.21
0.13
Phi coefficient
1.79-7.94
2.59-6.35
1.52-3.58
95% CI
0.001
<0.0001
<0.0001
P-value
Respiratory
(n = 29)
-
-
-
*
*
Pearson’s χ2
4.96
2.71
Odds ratio
-
-
Phi coefficient
2.19-11.26
1.13-6.51
95% CI
0.001
0.031
P-value
GI#
(n = 89)
-
-
-
-
*
Pearson’s χ2
4.13
Odds ratio
-
Phi coefficient
2.48-6.87
95% CI
<0.0001
P-value
#Gastro-Intestinal; *criteria for Pearson-Chi square test were not met, therefore the Fisher’s
Exact Test was used; Confidence Interval
Table 4. Statistical analysis of the O.M.E.N.S. score in patients with extracraniofacial anomalies
Extracranio
facial
anomalies
(n = 462)
Vertebral
anomalies
(n = 275)
CNS
anomalies
(n = 105)
Circulatory
anomalies
(n = 205)
Respiratory
anomalies
(n = 29)
Gastro-
intestinal
anomalies
(n = 89)
Urogenital
anomalies
(n = 108)
Orbit*
0.086
0.120
0.022
0.088
0.130
0.051
0.005
Pearson’s r
1.09
1.13
1.02
1.09
1.14
1.05
1.01
Odds ratio
0.97-1.22
1.00-1.28
0.85-1.23
0.95-1.25
0.84-1.54
0.87-1.27
0.84-1.12
95% CI
0.133
0.049
0.814
0.201
0.398
0.592
0.959
P-value
Mandible**
0.331
0.329
0.186
0.201
0.356
0.342
0.240
Pearson’s r
1.39
1.39
1.20
1.22
1.43
1.41
1.27
Odds ratio
1.21-1.61
1.19-1.62
0.97-1.50
1.03-1.45
0.91-2.23
1.11-1.79
1.02-1.59
95% CI
<0.0001
<0.0001
0.094
0.022
0.118
0.006
0.033
P-value
Ear*
0.101
0.101
-0.014
0.161
0.121
0.143
-0.008
Pearson’s r
1.11
1.11
0.99
1.18
1.13
1.15
0.99
Odds ratio
0.98-1.25
0.97-1.27
0.81-1.20
1.01-1.38
0.78-1.64
0.93-1.43
0.82-1.20
95% CI
0.10
0.146
0.889
0.046
0.524
0.189
0.934
P-value
Nerve*
0.233
0.238
0.107
0.188
0.048
0.292
0.236
Pearson’s r
1.26
1.27
1.11
1.21
1.05
1.34
1.27
Odds ratio
1.07-1.49
1.07-1.50
0.89-1.39
1.01-1.45
0.49-2.26
1.05-1.70
1.02-1.57
95% CI
0.005
0.005
0.340
0.045
0.902
0.017
0.033
P-value
Soft Tissue*
0.300
0.203
-0.114
0.319
0.567
0.497
0.182
Pearson’s r
1.35
1.23
0.89
1.38
1.76
1.64
1.20
Odds ratio
1.14-1.60
1.02-1.47
0.68-1.18
1.12-1.70
1.09-2.85
1.23-2.20
0.92-1.56
95% CI
0.001
0.031
0.421
0.003
0.020
0.001
0.173
P-value
*Orbit, Ear, Nerve, Soft Tissue score on the O.M.E.N.S. scale ; **Mandible score based on
Pruzansky-Kaban classification; Confidence Interval
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The wide spectrum of anomalies associated with hemifacial microsomia (HFM) has made systematic and inclusive classification difficult. We propose a nosologic system In which each letter of the acronym O.M.E.N.S. Indicates one of the five major manifestations of HFM. O for orbital distortion; M for mandibular hypoplasia; E for ear anomaly; N for nerve Involvement; and S for soft tissue deficiency. The O.M.E.N.S. system is easily adapted for data storage, retrieval, and statistical analysis. A retrospective study of 154 patients with HFM classified according to the O.M.E.N.S. system confirmed the concept that the mandibular deformity is the cornerstone of the anomaly. Statistical analysis demonstrated a positive association between mandibular hypoplasia and the severity of orbital, auricular, neural, and soft tissue involvement. This study did not confirm a previously reported predominance of gender or sidedness. Analysis of statistical correlations failed to substantiate a Goldenhar variant as a syndromic entity. Our analysis showed that palatal deviation is probably caused by muscular hypoplasia and not by weakness of a particular cranial nerve.
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Purpose Craniofacial microsomia (CFM) is a congenital malformation of structures derived from the first and second pharyngeal arches leading to underdevelopment of the face. However, besides the craniofacial underdevelopment, extracraniofacial anomalies including cardiac, renal and skeletal malformation have been described. The aim of this study is to analyse a large population of patients with regard to demographics, typical phenotypes including craniofacial and extracraniofacial anomalies, and the correlations between the different variables of this condition. Material and Methods A retrospective study was conducted in patients diagnosed with CFM with available clinical and/or radiographic images. All charts were reviewed for information on demographic, radiographic and diagnostic criteria. The presence of cleft lip/palate and extracraniofacial anomalies were noted. Pearson correlation tests and principal component analysis was performed on the phenotypic variables. Results A total of 755 patients were included. The male-to-female ratio and right-to-left ratio were both 1.2:1. A correlation was found among Pruzansky–Kaban, orbit and soft tissue. Similar correlations were found between ear and nerve. There was no strong correlation between phenotype and extracraniofacial anomalies. Nevertheless, extracraniofacial anomalies were more frequently seen than in the ‘normal’ population. Patients with bilateral involvement had a more severe phenotype and a higher incidence of extracraniofacial and cleft lip/palate. Conclusion Outcomes were similar to those of other smaller cohorts. Structures derived from the first pharyngeal arch and the second pharyngeal arch were correlated with degree of severity. Extracraniofacial anomalies were positively correlated with CFM. The findings show that bilaterally affected patients are more severely affected and should be approached more comprehensively.
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Oculo-auriculo-vertebral spectrum (OAVS OMIM164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s). Copyright © 2015. Published by Elsevier Masson SAS.