PEDIATRICS Vol. 99 No. 5 May 1997,
p. e9
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Detection of a 22q11.2 Deletion in Cardiac Patients Suggests a
Risk for Velopharyngeal Incompetence
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From the Divisions of * Human Genetics and Molecular Biology,
Cardiology, and ¶ Plastic and Reconstructive Surgery, Children's
Hospital of Philadelphia; and Departments of
Pediatrics,
§ Obstetrics and Gynecology, and # Surgery, University of Pennsylvania
School of Medicine, Philadelphia.
Objective. Conotruncal cardiac anomalies frequently occur in patients with DiGeorge or velocardiofacial syndrome. Additionally, these patients may have overt or submucousal cleft palate, as well as velopharyngeal incompetence (VPI). Previous studies have demonstrated that the majority of these patients have a submicroscopic deletion of chromosome 22q11.2. We hypothesized that a subpopulation of newborns and children with congenital heart defects caused by a 22q11.2 deletion are at a high risk for having unrecognized palatal abnormalities. Therefore, we proposed to evaluate a cohort of patients with conotruncal cardiac malformations associated with a 22q11.2 deletion to determine the frequency of palatal abnormalities.
Methods. We identified 14 deletion-positive patients with congenital cardiac defects who had no overt cleft palate. Of the 14 patients evaluated for the 22q11.2 deletion, 8 patients were recruited from a previous study looking for deletions among patients with isolated conotruncal cardiac anomalies. Informed consent was obtained in these cases. The remaining patients had the deletion study on a clinical basis, ie, conotruncal cardiac defect and an absent thymus, immunodeficiency, or minor dysmorphia appreciated by the clinical geneticist. These patients were evaluated by a plastic surgeon and speech pathologist looking for more subtle palatal anomalies such as a submucousal cleft palate, absence of the musculous uvuli, and VPI. Some patients underwent videofluoroscopy or nasendoscopy depending on their degree of symptoms and age. VPI was not ruled out until objective evaluation by a speech pathologist and plastic surgeon was obtained. In addition, the child had to be old enough to provide an adequate speech sample.
Results. Of the 14 patients evaluated, 6 patients older
than 1 year were found to have VPI. It is noteworthy that 3 of these patients were older than 5 years and had remained unrecognized until
this study. The remaining 6 patients had inconclusive studies based on
their age (younger than 26 months) and their inability to participate
in adequate speech evaluations. Two of these patients, however, had
histories of nasal regurgitation suggesting VPI and, in addition, had
incomplete closure of the velopharyngeal mechanism during crying and
swallowing observed during nasendoscopic examination
consistent with
the diagnosis of VPI. Thus, 8 of 14 patients evaluated had evidence of
VPI by history and examination. The remaining 6 patients will require
further study when they are older before a definitive palatal diagnosis
can be made.
Conclusions. A significant number of patients with a 22q11.2 deletion in a cardiac clinic may have unrecognized palatal problems. Recognition of such abnormalities will afford patients the opportunity for intervention as needed, ie, speech therapy and/or surgical intervention. Notably, two of our patients with findings suggesting VPI were infants and will, therefore, be afforded the opportunity for close follow-up and early intervention. Furthermore, three school-aged children had palatal abnormalities that were unrecognized until this study. Thus, we recommend 22q11.2 deletion studies in patients with conotruncal cardiac malformations, followed by extensive palatal and speech evaluations when a deletion is present. chromosome 22q11.2 deletion, DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, Opitz G/BBB syndrome, conotruncal cardiac anomalies, cleft palate, velopharyngeal incompetence.
Cardiac anomalies are often observed in association with other malformations and as a feature of well-defined genetic syndromes. Frequently, the cardiac abnormality is the first presenting sign of a genetic disorder and may remain the predominant medical problem in the child's early years. Because of this, attention to or recognition of other problems may be overlooked. Diagnosis of a syndrome may not be made until later in life, if at all. In many cases, the early diagnosis of a syndrome is beneficial in guiding the total treatment of the child as well as in providing the family with accurate genetic counseling.
Conotruncal cardiac anomalies, including interrupted aortic arch type
B, truncus arteriosus, and tetralogy of Fallot, are seen as part of
DiGeorge syndrome (DGS). Additionally, some patients may have a
conoventricular septal defect or a right-sided aortic arch with
aberrant subclavian arteries.1 DGS is a developmental field defect of the third and fourth pharyngeal pouches, which often
includes thymic and parathyroid gland aplasia or hypoplasia, mild
facial dysmorphia, and palatal abnormalities.2,3 The etiology of DGS is heterogeneous. There have been reports of autosomal dominant, autosomal recessive, and X-linked inheritance as well as an
association with maternal diabetes.4 In addition,
cytogenetic abnormalities have been observed in patients with DGS. Many
of the chromosomal abnormalities observed in affected children have been unbalanced translocations, which result in monosomy
22pter
q11.7 More recently, high-resolution
cytogenetic analysis and molecular studies using DNA dosage analysis or
fluorescence in situ hybridization (FISH) have demonstrated that the
vast majority of patients with DGS have interstitial or submicroscopic
deletions within chromosomal region 22q11.2.17 We have
detected microdeletions of 22q11.2 in approximately 90% of patients
with DGS referred for molecular analysis.20,21 Studies have
shown that FISH using chromosome 22q11.2-specific probes is an
efficient method for the detection of 22q11.2 deletions and can be
recommended as an adjunct to routine cytogenetic
analysis.20,22
Conotruncal defects, predominantly tetralogy of Fallot and conoventricular septal defects, have also been seen in association with velocardiofacial syndrome (VCFS).23 VCFS has been described as an autosomal dominant disorder in which, in addition to having cardiac anomalies, patients may present with overt or submucousal cleft palate, velopharyngeal incompetence (VPI), facial dysmorphia, and learning disabilities.24 Overlap between the features of DGS and VCFS, including cardiac anomalies, cleft palate, hypocalcemia, and immunodeficiency, suggested a common etiology and pathogenesis.27 Similar deletions of 22q11.2 have been detected in the majority of patients with VCFS.20,21,30,31
Because facial dysmorphia is either not appreciated or evident in the newborn period, the diagnosis of DGS or VCFS is frequently dependent on the presence of other findings, such as hypocalcemia, immunodeficiency, and overt cleft palate in patients with conotruncal cardiac malformations. In the absence of these clues, the diagnosis may be difficult. Furthermore, a submucousal cleft palate or VPI without overt cleft palate is often unrecognized in the preverbal child and may remain undetected in the older child, particularly if there is a learning disability. Therefore, children who continue to have these unrecognized problems may remain untreated, missing the opportunity for early speech intervention and/or early surgical correction.
We hypothesized that a subpopulation of newborns and children with congenital heart defects and a 22q11.2 deletion are at high risk for having unrecognized palatal abnormalities. Therefore, we proposed to evaluate a cohort of patients with conotruncal cardiac malformations associated with a 22q11.2 deletion to determine the frequency of palatal abnormalities.
Patients with conotruncal cardiac anomalies underwent studies for the detection of a microdeletion of chromosome 22q11.2 (Fig 1) as previously described.20 Children with an overt cleft palate were excluded from the present study. The first 14 cardiac patients with 22q11.2 deletions were referred for palatal evaluations (Table 1). Eight patients were recruited from a previous study looking for deletions among patients with isolated conotruncal cardiac anomalies.32 The remaining patients had the deletion study on a clinical basis, ie, conotruncal cardiac anomaly and an absent thymus, immunodeficiency, or minor dysmorphia appreciated by the clinical geneticist. These patients are also enrolled in a long-term prospective study to examine phenotype-genotype correlations.
Fig. 1. Fluorescence in situ hybridization demonstrates one normal chromosome 22 (arrow) and one deleted chromosome 22 (half arrow).
[View Larger Version of this Image (76K GIF file)]
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Table 1. Cardiac Findings in 14 Patients With 22q11.2 Deletion Referred for Palatal Evaluation |
Table 2.
Results of Palatal Evaluations in 14 Patients With Cardiac Anomalies
and 22q11.2 Deletion
Fig. 2.
Flow diagram of palatal evaluation.
[View Larger Version of this Image (16K GIF file)]
Fig. 3.
With nasendoscopy, a normal velopharyngeal port is visualized at rest,
demonstrating a normal musculous uvuli (A, arrow) and a normal closure
during crying or swallowing (B). An abnormal velopharyngeal port is
visualized at rest, demonstrating the absence of the musculous uvuli
(C) and an abnormal attempt at closure during crying or swallowing
(D).
[View Larger Version of this Image (102K GIF file)]
Of the 14 patients evaluated, 7 were older than 1 year. Of
these 7 patients, 6 were found to have VPI (Table 2). It
is noteworthy that 3 of these patients, older than 5 years, were
unrecognized until this study. One of the 3 patients subsequently has
undergone a pharyngoplasty, whereas surgical intervention has been
recommended for the other 2 patients. Although it is generally
difficult to diagnose VPI in children younger than 1 year, 2 patients in this age group had histories of nasal regurgitation
suggesting VPI. In addition, incomplete closure of the velopharyngeal
mechanism during crying and swallowing was observed during
nasendoscopic examination
consistent with the diagnosis of VPI.
However, these 2 patients will still require complete speech
evaluations before the initiation of treatment plans, which most likely
will include surgical correction and speech therapy. Six patients,
younger than 26 months, were considered too young to assess to our
satisfaction, based on our inability to perform complete speech
evaluations. Thus, a total of 8 of 14 patients evaluated had evidence
of VPI by history and examination. The remaining 6 patients will
require further study when they are older before a definitive palatal diagnosis can be made.
Fig. 4.
Four infants with diagnoses of a 22q11.2 deletion have subtle
dysmorphia, including prominent ears, a bulbous nasal tip, and malar
flatness.
[View Larger Version of this Image (118K GIF file)]
Fig. 5.
Four preschool-aged children with the 22q11.2 deletion have varying
degrees of facial dysmorphia, including the emergence of a prominent
nasal root.
[View Larger Version of this Image (121K GIF file)]
Fig. 6.
Three school-aged children with the 22q11.2 deletion have bulbous nasal
tips and prominent nasal roots with varying degrees of ear
malformations.
[View Larger Version of this Image (80K GIF file)]
Studies by us and others have reported an association among
DGS, VCFS, and chromosome 22q11.2
deletions.17,18,30,31 The commercial availability of a
FISH assay for the detection of this deletion has made definitive
diagnosis possible in most patients with clinical histories of DGS or
VCFS. In addition, such studies may now be helpful in patients with
conotruncal cardiac anomalies for the purpose of treatment and
recurrence risk counseling. If a 22q11.2 deletion is detected, patients
may be offered clinical evaluations before a problem becomes evident
and, thus, may be offered early intervention. For example, it is
noteworthy that two of our patients with findings suggesting VPI were
infants and will, therefore, be afforded the opportunity for close
follow-up and early intervention as indicated. These two patients,
along with the other five in the younger age group, will provide us with unbiased prospective data to determine the efficacy of early recognition of and intervention for palatal abnormalities. Furthermore, it is of interest that the three school-aged children (older than 5 years) had unrecognized palatal abnormalities until this study.
Received for publication Feb 5, 1996; accepted May 20, 1996.
Reprint requests to (D.M.M.-M.) Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.
This study was supported in part by grants DC02027 and HL51533 from the National Institutes of Health, a grant from the Cleft Palate Foundation, and by funds from Oncor.
DGS, DiGeorge syndrome. FISH, fluorescence in situ hybridization. VCFS, velocardiofacial syndrome. VPI, velopharyngeal incompetence.
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Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
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