Shprintzen syndrome

Abstract

Velocardiofacial syndrome is classically characterized by clefting of the secondary palate, cardiac defects, learning disabilities, and facial dysmorphism. Knowledge of this syndrome is of significant importance to otolaryngologists because a failure to recognize it prior to head and neck surgery can result in serious iatrogenic injury, including velopalatal insufficiency and damage to anomalous carotid arteries. To illustrate these issues, we describe the case of a 5-year-old boy with velocardiofacial syndrome. We also review the literature on velocardiofacial syndrome, which is not very extensive, perhaps because it is often difficult to recognize.

Introduction

Velocardiofacial syndrome is a relatively common, likely underdiagnosed disorder that is believed to be present in approximately 1 in 3,000 individuals. (1) It is classically characterized by clefting of the secondary palate, cardiac defects, learning disabilities, and facial dysmorphism. (2-4) Velocardiofacial syndrome is the most common syndrome associated with clefting of the secondary palate, but there is a paucity of reporting in the otolaryngology literature. (3) This lack of discussion might be attributable in part to the fact that velocardiofacial syndrome is often difficult to diagnose because of its wide range of phenotypic variance.

Recognition and knowledge of this syndrome are of significant importance to the otolaryngologist. First, adenoidectomy in a patient with unrecognized velocardiofacial syndrome can lead to the formidable complication of iatrogenic velopalatal insufficiency. Second, safe pharyngeal surgery in a velocardiofacial syndrome patient who already has velopalatal insufficiency must be preceded by careful evaluation for frequently associated vascular anomalies. To illustrate these issues, we describe the case of a 5-year-old boy whom we treated at Walter Reed Army Medical Center in Washington, D.C.

Case report

A 5-year-old white boy with known velocardiofacial syndrome was brought to our institution for evaluation and treatment of severe hypernasal speech. The patient's parents reported that his symptom had been lifelong. The child also had an overall long-standing speech delay that had been diagnosed by his primary care physician. The patient's significant medical and surgical history included repair of the retralogy of Fallot at the age of 9 months, repair of an umbilical hernia at 3 years, and a reimplantation of the ureter for vesicoureteral reflux at 3 years and 6 months. Approximately 6 months before his current evaluation, he had undergone a tonsillectomy for hypertrophy that was believed to have caused significant palatal dysfunction. The patient was routinely taking no prescription medications, and he had no known drug allergies.

On physical examination, the boy had a long vertical face, low-set ears, narrow palpebral fissures, a broad nasal bridge, and a fleshy nasal tip (figure 1, A). Oral examination revealed a hypotonic palate and well-healed tonsillar fossae (figure 1, B). Nasopharyngoscopic examination demonstrated a moderately large adenoid pad and a global decrease in the motion of the velum and lateral pharyngeal walls with speech. His nasopharynx closed with swallowing. The posterior nasopharyax was noted to exhibit significant bilateral pulsations medially to the posterior tonsillar pillars and extending superiorly to the adenoid pad. The nasal velum was flat in appearance, and diastasis of the musculature was observed.

Videofluoroscopic examination confirmed the presence of a concentric nasopharyngeal gap during articulation as well as poor movement of the velum and lateral pharyngeal walls. Magnetic resonance angiography (MRA) and standard magnetic resonance imaging (MRI) demonstrated medialization of both internal carotid arteries, with the right artery extending directly behind the pharynx at the level of the body of C2 (figure 2).

The child was brought to the operating room for an examination under anesthesia and possible pharyngoplasty. During direct visual examination, he was noted to have continued prominent submucosal pulsations directly posterior to the posterior tonsillar pillars. It was determined at that time that the creation of any potential pharyngeal flap would have posed a direct risk to the carotid vasculature, and the procedure was terminated. The boy has since been referred for a trial with a palatal obturator.

Discussion

Clefting. Although patients with velocardiofacial syndrome almost uniformly have clefting of the secondary palate, it is frequently an "occult" clefting that can be observed only on nasopharyngoscopy. In one of the early series that addressed this syndrome, Shprintzen et al studied 39 children and found that 11 had overt clefts, 13 had obvious submucosal clefts, and the remaining 15 had occult clefts. (5) Features of the occult cleft palate include a flat nasal velum (reflecting a hypoplastic musculus uvulae), with or without visible diastasis of the velar musculature. Finkelstein et al examined 21 patients with velocardiofacial syndrome and velopalatal insufficiency and found occult clefting in 14 of them. (3)

Cardiac defects. Cardiac anomalies have been reported to occur in 66 to 84% of patients with velocardiofacial syndrome. (3,5,6) Typical abnormalities include ventricular septal defects, the tetralogy of Fallot, and a right-sided aorta. Less common manifestations include atrial septal defects, patent ductus arteriosus, and anomalous subclavian arteries. (3) Goldberg et al hypothesized that many children with velocardiofacial syndrome are unrecognized because its immediate life-threatening signs and symptoms often draw the initial "focus of attention and diagnostic expertise" while identification of the full syndrome is not carried out. (6)

Learning disabilities. Shprintzen et al published the first descriptive case series of patients with velocardiofacial syndrome and reported that 11 of 12 patients had learning disabilities. (2) These handicaps included academic and motor disabilities as well as mental retardation in two children. In subsequent case series, learning disabilities have been reported in more than 90% of affected patients, (5,6) and mild to moderate mental retardation has been found in more than 40% (7) A very high prevalence of psychiatric conditions, including depression and bipolar disorders, has also been reported. (1,6)

Facial dysmorphism. The classic facial characteristics of velocardiofacial syndrome include a prominent nose with a "broad, often squared" nasal root, narrow alar base, narrow palpebral fissures, flattened malar eminences, vertical maxillary excess, and a retruded mandible. (5) Wide variance in these findings is seen. In their series of 21 patients, Finkelstein et al noted that only 11 had the full spectrum of facial anomalies; the most common signs were narrow palpebral fissures and a high nasal bridge. (3) Other syndromes with similar facies include myotonic dystrophy, Langer-Giedion syndrome, DiGeorge syndrome, and trichorhinophalangeal syndrome. (5)

Other features. Velocardiofacial syndrome includes a number of other diverse and highly variable features. Finkelstein et al reported that as infants, more than half of affected patients had a history of feeding difficulty and nearly three-quarters had a history of hypotonia. (3) Carotid artery medialization is present in 14 to 65% of patients. (3,8,9) Conductive hearing loss is frequently noted and is often believed to be related to the eustachian tube dysfunction that is presumed to be present in children with cleft palates. (5) Immune dysfunction appears to be a common finding in these children. These immune disorders have been linked to T-cell dysfunction and have been reported to manifest as recurrent pneumonia or chronic upper respiratory (10-12) Other less common associated findings include pharyngeal hypotonia, slender hands and digits, small stature, Pierre Robin sequence, inguinal hernias, and umbilical hernias. (3,5,6) The ultimate diagnosis of velocardiofacial syndrome is therefore based on a combination of features rather than a specific number of them.

Etiology. The etiology of velocardiofacial syndrome has been the subject of highly complex evaluations, and the syndrome is now strongly linked to microdeletions on the long arm of chromosome 22, an area that has yet to be fully defined. These deletions have been confirmed in the vast majority of cases by fluorescent in situ hybridization studies. (13-15) It has been surmised that patients who do not have detectable deletions likely have smaller, as yet undetectable changes in this same region. (13) (It is interesting that velocardiofacial syndrome sequence deletions appear to be similar to those noted in DiGeorge syndrome, which is linked to malformations of the fourth and fifth pharyngeal arches. In both syndromes, conotruncal cardiac anomalies are often noted. (13) Although some evidence of autosomal-dominant inheritance has been noted, most patients with velocardiofacial syndrome do not report a family history suggestive of this syndrome. (13,15)

Diagnosis. The initial recognition of velocardiofacial syndrome is important to the otolaryngologist, but doing so is challenging. While most authors of published case series initially identified such children on the basis of velopalatal insufficiency, there is almost certainly a population of these patients in whom minimal or no hypernasality can be noted on examination. These children can appear with the entire range of ordinary otolaryngologic diseases. Indeed, they can have a disproportionate level of middle ear disease and could certainly seek evaluation based on this problem alone. Adenoidectomy in this unrecognized patient subpopulation could lead to an iatrogenic velopalatal insufficiency. This was illustrated in two series of patients with postadenoidectomy velopalatal insufficiency; in both studies, the authors found that submucosal clefting was the most common predisposing factor to this complication. (16,17) Recognizing velocardiofacial syndrome and avoiding adenoidectomy in these patients would p revent this potentially severe problem.

To identify this "subtle subpopulation," the otolaryngologist must rely on a careful history and physical examination during the initial clinic visit. Parents should be questioned closely regarding their child's birth and developmental histories. Any evidence of significant infantile hypotonia, feeding difficulties, or delayed or impaired speech development should be of concern. Any history of cardiac pathology is important to note. On physical examination, careful evaluation for facial dysmorphism and close inspection of the dynamic oral palate are both brief but vital steps. Any cause for concern based on these findings should lead to a full nasopharyngoscopic examination to rule out palatal clefting.

Management. Although the management of patients with subtle velocardiofacial syndrome must be focused on avoiding iatrogenic velopalatal insufficiency, the focus of managing children with a more severe manifestation is often directed to the treatment of already existing velopalatal insufficiency. As a manifestation of velocardiofacial syndrome, velopalatal insufficiency is a very common and often central symptom. Indeed, velocardiofacial syndrome must be high on the list of differential diagnoses for all children who are evaluated for velopalatal insufficiency alone. In a study of 246 consecutive patients with velopalatal insufficiency, Witzel and Posnik found that nearly 10% of these cases were secondary to velocardiofacial syndrome. (17)

In patients with velocardiofacial syndrome and velopalatal insufficiency, pharyngeal motion has been reported to be highly variable. In their study of 21 patients with velocardiofacial syndrome and velopalatal insufficiency, Finkelstein et al noted no movement of the lateral pharyngeal walls in six patients, mild movement in 11, and normal movement in only four. (3) One constant observation was that a short, flat velum appeared to be abnormally thin on lateral-view videofluoroscopy.

Treatment options for patients with velocardiofacial syndrome and velopalatal insufficiency range from speech therapy alone to palatal obturators and surgery. Surgical options include pharyngeal flap surgery, palatal lengthening, and intravelar veloplasty.

Preoperative evaluation. Many patients with velocardiofacial syndrome require pharyngeal surgery, and the surgeon must identify any anatomic anomalies before the procedure can be performed. One of the most common and relevant anomalies is medialization of the internal carotid arteries, which has been reported to occur in 14 to 65% of patients with velocardiofacial syndrome. (3,8,9) Again, medialized carotids must be located and defined prior to surgical intervention.

The method of investigation is controversial, but preoperative visualization of the nasopharynx must be part of any initial clinic work-up. Close endoscopic examination must be performed to look for evidence of visible pulsations, which might reflect a dangerous proximity of the pharyngeal walls to the carotid vessels. In a retrospective review of 39 patients with velocardiofacial syndrome, Witt et al noted visible posterior pharyngeal pulsations in 10. (18) All 10 were still able to undergo either pharyngeal flap surgery or sphincter pharyngoplasty without complications. None had undergone preoperative imaging. Witt et al argued that imaging techniques do not provide any significant additional information over and above that obtained by physical examination and that it only adds significantly to the cost of treatment.

While Witt et al contended that examination alone is satisfactory in determining the safety of flap creation, others have strongly advocated preoperative imaging to identify the full course of the carotids and their relation to the posterior pharyngeal wall. For example, Mitnick et al performed nasopharyngoscopy and MRA on 20 children with velocardiofacial syndrome and velopalatal insufficiency and identified medialization of the carotids in 12 and pulsations in 10. (9) Most impressive was the fact that they found no correlation between the pulsations and the location of the carotids on MRA. Indeed, six patients in that study had medially placed carotid arteries and no noted pulsation, and three had pulsations without medialization. Mitnick et al contended that visualization alone is not a dependable method of localizing possible aberrant arteries. (9)

In another report, Ross et al took a moderate position and recommended imaging only for those patients who have clinically apparent posterior pharyngeal pulsations. (8) In their study, 25 children with velocardiofacial syndrome, velopalatal insufficiency, and obvious posterior pharyngeal pulsations were examined with computed tomographic angiography. The authors found that the mean level of deviation of medialized carotids was at the level of the body of C2. These arteries were determined to be an average of 4 to 5 mm from the pharyngeal lumen; 18 of the 50 arteries were within 3 mm of the lumen. Ross et al correlated this finding with their observation that their flaps consistently extended to the level of the C2-C3 junction. With this in mind, they noted that their standard pharyngeal flap would be "safe" in 52% of patients and that a modified flap would be "safe" in an additional 28%. In the remaining 20% of patients, they believed that the medialization was high enough to preclude any safe flap placement. They argued that their protocol provides the surgeon with sufficient criteria to tailor treatment--criteria that are not provided by clinical examination only. (8)

Our patient had come to us with previously identified velocardiofacial syndrome. We chose MRA to evaluate the pulsations that we noted on examination, and it provided important information regarding the aberrant position of our patient's carotid arteries. In this particular case, the right artery was noted to be directly behind the pharynx at the level of C2. Because the vessel appeared to be not directly submucosal on examination by office flexible nasopharyngoscopy, we felt that it would be possible to create a carefully raised flap with the palatopharyngeal muscles by sphincter pharyngoplasty. However, our initial intraoperative assessment showed that this technique could also violate the artery, and the procedure was therefore terminated.

While our case was relatively classic and severe, it should be emphasized that velocardiofacial syndrome of various degrees of severity can be seen by a number of different healthcare providers. Knowledge of this syndrome's seemingly unassociated manifestations is imperative to recognizing it. The otolaryngologist must use significant caution if any of these manifestations are found in a child who is undergoing an evaluation for adenoidectomy. A detailed investigation in such a situation can prevent iatrogenic velopalatal insufficiency. For the otolaryngologist who is considering pharyngeal flap surgery for a patient with velopalatal insufficiency, the same caution must be taken to identify this syndrome and, if it is present, to fully evaluate each patient for dangerous anatomic anomalies.

References

(1.) Papolos DF, Faedda GL, Veit S, et al. Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: Does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 1996;153:1541-7.

(2.) Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: Velo-cardio-facial syndrome. Cleft Palate J 1978;15:56-62.

(3.) Finkelstein Y, Zohar Y, Nachmani A, et al. The otolaryngologist and the patient with velocardiofacial syndrome. Arch Otolaryngol Head Neck Surg 1993;119:563-9.

(4.) Bluestone CD, Stool SE, Kenna MA, eds. Pediatric Otolaryngology. 3rd ed. Philadelphia: W.B. Saunders, 1996:1625.

(5.) Shprintzen RJ, Goldberg RB, Young D, Wolford L. The velocardio-facial syndrome: A clinical and genetic analysis. Pediatrics 1981;67:167-72.

(6.) Goldberg R, Motzkin B, Marion R, et al. Velo-cardio-facial syndrome: A review of 120 patients. Am J Med Genet 1993;45:313-9.

(7.) Swillen A, Devriendt K, Legius E, et al. Intelligence and psychosocial adjustment in velocardiofacial syndrome: A study of 37 children and adolescents with VCFS. J Med Genet 1997;34:453-8.

(8.) Ross DA, Witzel MA, Armstrong DC, Thomson HG. Is pharyngoplasty a risk in velocardiofacial syndrome? An assessment of medially displaced carotid arteries. Plast Reconstr Surg 1996;98:1182-90.

(9.) Mitnick RJ, Bello JA, Golding-Kushner KJ, et al. The use of magnetic resonance angiography prior to pharyngeal flap surgery in patients with velocardiofacial syndrome. Plast Reconstr Surg 1996;97:908-19.

(10.) DePiero AD, Lourie EM, Berman BW, et al. Recurrent immune cytopenias in two patients with DiGeorge/velocardiofacial syndrome. J Pediatr 1997;131:484-6.

(11.) Duke SG, McGuirt WF, Jr., Jewitt T, Fasano MB. Velocardiofacial syndrome: Incidence of immune cytopenias. Arch Otolaryngol Head Neck Surg 2000;126:1141-5.

(12.) Williams MA, Shprintzen RJ, Rakoff SJ. Adenoid hypoplasia in the velo-cardio-facial syndrome. J Craniofac Genet Dev Biol 1987;7:23-6.

(13.) Driscoll DA, Salvin J, Sellinger B, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: Implications for genetic counselling and prenatal diagnosis. J Med Genet 1993;30:813-7.

(14.) Driscoll DA, Spinner NB, Budarf ML, et al. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 1992;44:261-8.

(15.) Kelly D, Goldberg R, Wilson D, et al. Confirmation that velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11. Am J Med Genet 1993;45:308-12.

(16.) Croft CB, Shprintzen RJ, Ruben RJ. Hypernasal speech following adenotonsillectomy. Otolaryngol Head Neck Surg 1981;89:179-88.

(17.) Witzel MA, Posnick JC. Patterns and location of velopharyngeal valving problems: Atypical findings on video nasopharyngoscopy. Cleft Palate J 1989;26:63-7.

(18.) Witt PD, Miller DC, Marsh JL, et al. Limited value of preoperative cervical vascular imaging in patients with velocardiofacial syndrome. Plast Reconstr Surg 1998;10l:1184-95.

From the Department of Otolaryngology--Head and Neck Surgery, Walter Reed Army Medical Center, Washington, D.C.

Reprint requests: Benjamin B. Cable, MD, University of Iowa Hospitals and Clinics, PFP 21202, 200 Hawkins Dr., Iowa City, IA 52242. Phone: (319) 356-3612; fax: (319) 356-4547; e-mail: benjamincable@hotmail.com

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or of the Department of Defense.

This work was conducted at Walter Reed Army Medical Center in Washington, D.C. No specific funding was granted for the preparation of this article. This work was originally presented at the annual meeting of the Society for Ear, Nose, and Throat Advances in Children; December 1998; Portland, Ore.

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