Shprintzen syndrome

Velocardiofacial syndrome (VCFS) is a rarely discussed, but important, congenital condition for otolaryngologists to recognise. Commonly caused by a deletion on the long arm of chromosome 22, it results in cardiac anomalies of varying severity, dysmorphic facial features and palatal dysfunction, as well as growth and intellectual delay. VCFS is the most common syndrome associated with soft palate anomalies, especially submucous clefts. Patients often present in early childhood with speech difficulties, otitis media and recurrent infections. While these may require treatment, adenoidectomy in VCFS patients may result in significant velopharyngeal insufficiency (VPI).

The present study studied the genotype, detailed phenotypical features and relevant investigations of a cohort of 26 patients with VCFS in order to determine the characteristic features that are particularly relevant to the otolaryngologist. While 62% of patients exhibited the typical facial dysmorphism and 38% had cardiac anomalies, 88% of our cohort had VPI on presentation with 4/26 cleft palates and 6/26 submucous clefts. Persistent otitis media was present in 62%, and 9 patients required palate surgery (2 for VPI following adenoidectomy). We discuss the phenotypic and genetic features of this syndrome that assist with diagnosis, and detail our assessment for submucous cleft palate.

The recognition and appropriate management of patients with velocardiofacial syndrome (VCFS) is an important challenge for otolaryngologists, especially those dealing with children. Affected patients are frequently referred for an otolaryngological opinion due to their predisposition to otitis media with effusion, recurrent upper respiratory tract infections, and speech and swallowing problems. The VCFS facial appearance may resemble so called "adenoid facies" (Lipson et al 1991). The hypernasal voice may be misconstrued as obstructive and erroneously attributed to adenoid enlargement. The 'catch 22' for the clinician is that the underlying pathology is usually subtle palatal dysfunction. Attempted remedy of these problems by adenoidectomy may therefore create or potentiate significant velopharyngeal insufficiency (VPI).

VCFS is an autosomal dominant genetically inherited disorder initially described by Shprintzen (Shprintzen et al 1978). It has been grouped with the Di George syndrome and conotruncal anomaly face syndrome under the acronym CATCH 22 (Wilson et al 1993, Wulfsberg et al 1996). CATCH 22 describes the phenotype-Cardiac anomalies, Abnormal facies, Thymic hypoplasia, Cleft palate and Hypocalcaemia. The common genotypic anomaly is a deletion on the long arm of chromosome 22 (#22qll.21-qll.23). Expression of the phenotype may vary from lethal cardiac malformations to mild palatal dysfunction. Whereas in Di George syndrome thymic hypoplasia with resultant infections is a primary feature, in VCFS the facial features, cardiovascular manifestations, developmental delay and palate anomalies are usually most prevalent.

By undertaking a detailed clinical and genetic evaluation of a cohort of Australian patients with VCFS, the present clinical study aims to analyse and present the characteristic features of this condition especially highlighting the associated otolaryngological implications. We emphasise the need for the otolaryngologist to be aware of the often subtle phenotypic features of this syndrome, particularly velopharyngeal dysfunction, which may require early therapeutic intervention and which would be worsened by adenoidectomy.

Method

The present clinical research project was based on a cohort of patients with velocardiofacial syndrome (VCFS) managed at Hunter Genetics and John Hunter Children's Hospital. Patients included in this series were deemed to have VCFS based upon classical phenotypic features with and without detected specific chromosomal deletions. Most patients presented with speech or feeding difficulties due to palatal dysfunction. VCFS was suspected when these were associated with developmental delay, characteristic appearance of the face and other parts of the body and, in some cases, cardiovascular anomalies. A medical geneticist independently confirmed the diagnosis in each case.

The typical facial characteristics of VCFS include a long oval face with flat malar eminences, small mouth and mild micrognathia, long broad prominent nose with a bulbous tip and small alae nasi, almond shaped eyes with hypertelorism and low set small cupped ears with overfolded helices (Figure 1). Spindle shaped or tapered fingers, cardiac and urological anomalies, inguinal herniae, growth delay and learning problems are also frequently described. The incidence and expression of these malformations are highly variable and may be quite abstruse.

In order to characterise the genetic anomalies, phenotypic features and otolaryngological manifestations of VCFS, detailed assessment and investigations were acquired (Table 1). Patients underwent detailed otolaryngological examination, review by a geneticist and, when appropriate, assessment by a paediatrician, cardiologist, speech pathologist and psychologist as well as audiometry, haematology, echocardiography and renal ultrasound.

Chromosomal assays of patients were performed using venous blood samples collected in standard heparin tubes. Peripheral blood leucocyte cultures with banding studies were used to confirm a normal 46,XX or 46,XY karyotype. In order to detect a chromosome 22q11.21q11.23 deletion, Fluorescent In Situ Hybridisation (FISH) analysis was performed using a cosmid probe corresponding to the TUPLE 1 locus within the Di George region of chromosome 22. A 22q11 deletion was diagnosed if hybridisation signals were not detected on one arm of their chromosome 22 (Figure 2). If the deletion was demonstrated, the parents were offered FISH testing to assist genetic counselling.

Assessment of velopharyngeal dysfunction included a careful history of feeding difficulties, nasal regurgitation and speech development. As well as a routine otolaryngological examination, particular attention was given to the appearance and movement of the uvula and palate. Flexible nasal endoscopy enabled direct evaluation of adenoid tissue, dimensions of velopharyngeal closure, and evidence of a submucous cleft palate. When indicated, VPI was confirmed by video-fluroscopy and the clinical sequelae quantified by objective speech pathology assessment.

Results

The study cohort consisted of 26 patients (15 females and 11 males) with VCFS. Three adult patients were diagnosed following referral for genetic counselling or family screening. The remaining patients were children whose age at diagnosis ranged from birth to 13 years with a mean of 4 years. Due to our specialised interest, most patients (22/26, 85%) initially presented with velopharyngeal anomalies (Table 2). Two patients were referred having developed VPI following adenoidectomy. While one of these patients had an evident submucous cleft, the other had no detectable anatomical palate anomaly. Both, however, had other typical phenotypic features of VCFS and both had the #22q11.2 deletion.

Velopharyngeal insufficiency (VPI)

23/26 (88%) patients had clinically apparent VPI ranging from subtle hypernasal speech to hypemasality severe enough to affect speech intelligibility and/or cause nasopharyngeal regurgitation. Twelve patients had no detectible anatomical malformation of the palate but demonstrated hypotonicity of the soft palate with velopharyngeal valve insufficiency on speech assessment and fluoroscopy (Table 3). In other cases, poor function was associated with slight variations such as a narrow arched or short palate. Four patients had an overt palatal cleft and 5 a submucous cleft palate (4 evident and 1 occult). A bifid uvula was seen in 4 patients, 3 of whom had a submucous cleft (Figure 3).

Other Otolaryngological features

Four patients experienced persistent upper respiratory infections (>7/year) requiring regular medical treatment and 3 had undergone tonsillectomy. One patient with obstructive sleep apnoea, following repair of a cleft palate, was cured with a partial adenoidectomy; another with nasal cavity stenosis required nocturnal CPAP (continuous positive airway pressure). Middle ear pathology was a common finding with 16/26 (62%) of patients suffering recurrent acute otitis media and conductive hearing loss due to chronic otitis media with effusion. This was particularly associated with palatal anomalies and many patients required placement of ventilation tubes. One patient had a bilateral sensorineural hearing loss. Another had extremely narrow external auditory canals. No case of laryngeal webbing or deformity was seen. One patient had neck webbing. Anomalous medial placement of the carotids was not detected on examination for pharyngeal pulsation nor was it found in those patients who were investigated with echocardiography or underwent pharyngoplasty (Table 4).

Phenotypic features

Growth delay was evident with 12/26 (46%) patients falling below the 3rd centile for height and 15/26 (58%) were of short stature. Sixteen patients exhibited the classic facies (Figure 1). Two patients were microcephalic, 2 others had micrognathia and three patients had expressionless, hypotonic faces (Table 5). Other phenotypic features (Table 4) included obvious spindle shaped or tapered fingers with small nails.

Associated anomalies

Varying degrees of neuromuscular and developmental delay occurred in many of our VCFS patient group. These included hypotonia in infancy (10/26), expressive speech delay (5/26), and learning problems (23/26, 88%). Congenital cardiac anomalies were detected in 10 patients, of whom half had multiple abnormalities (Table 4). Other than a single case of vesico-ureteric reflux, no urological problem was found. Five patients had inguinal herniae and 2 had gastro intestinal motility problems. Hypoparathyroidism with low serum calcium was detected in 4 patients.

Genetics and inheritance

Chromosomal analysis was performed for 18 patients. A normal karyotype (46,XX or 46,XY) was demonstrated in all patients. On FISH analysis, 15 exhibited hemizygosity indicating the 22q11.2 deletion (Table 6). Assessment of family members revealed a propensity for maternal carriage of the chromosome 22q11.2 deletion genotype as well as phenotypic expression of VCFS.

Surgical management and speech therapy

Velopharyngeal insufficiency was initially managed with speech therapy in 18 of 23 children. Nine patients (40%) required surgery for VPl. Four had repair of an overt cleft palate and 5 had repair of a submucous cleft with a pharyngoplasty. The 2 children who developed significant VPI following adenoidectomy both required pharyngoplasty. Sixteen patients required myringotomy and insertion of ventilating tubes, I had a mastoidectomy, and 2 came to partial adenoidectomy for obstructive sleep apnoea (Table 7). Other operations required included 5 hernia repairs and 9 open cardiac procedures.

Discussion

While the acronym "CATCH 22" (Cardiac anomalies, Abnormal Facies, Thymic hypoplasia, Cleft palate and Hypocalcaemia) provides a useful guide to the classical phenotypic traits associated with the 22q11.2 deletion, it is important to realise that most patients exhibit partial or mild expression of these anomalies. As inherent in the name "velocardiofacial syndrome", the most recognised presenting features are palatal dysfunction with hypernasal speech, cardiac anomalies and the typical facial dysmorphism. Particularly prevalent phenotypic characteristics of VCFS in our patient cohort were the typical facial features (40%) with almond shaped eyes, broad bulbous nose, small alae and small mouth. Short stature (58%), learning difficulties (42%) and cardiac anomalies (38%) were also frequent. A multi-centre European collaborative study found 36% of patients were below the 3rd growth centiles, 32% had VPI and 75% had cardiac anomalies (Ryan et al 1997). The high incidence of VPI (88%) in our series may be ascertainment bias due to our interest in palatal dysfunction.

Echocardiography is indicated in all newly diagnosed VCFS patients. Renal ultrasound is also recommended as there is a reported incidence of up to 36% of urogenital anomalies (Ryan et al 1997). VCFS-related learning difficulties may warrant special educational intervention and a 10% incidence of psychiatric disorders requires ongoing vigilance (Goldberg et al 1993, Kok et al 1995).

VCFS is the most common genetic syndrome associated with clefts of the soft palate (Shprintzen et al 1981). Submucous cleft palates (which may require nasendoscopy for diagnosis) are the most prevalent abnormality (Finglestein et al 1992). Resulting incompetence or insufficiency of the velopharyngeal valve mechanism leads to hypernasal speech and/or nasal regurgitation with feeding difficulty during infancy. A history of these problems should raise suspicion and a search for the other characteristic features of VCFS particularly before contemplating surgery in the nasopharynx.

Adenoidectomy is one of the most common otolaryngological procedures performed in Australia. Prevailing indications include persistent or recurrent otitis media, recurrent adenoiditis, secondary sinusitis and significant nasal obstruction. As has been demonstrated with our cohort, such problems are particularly frequently encountered in children with VCFS. Patients with this syndrome also have an exceedingly high incidence of palatal anomalies which may not be clinically obvious. Should palate dysfunction be overlooked and 'routine' adenoidectomy performed, significant velopharyngeal insufficiency may occur, which could result in unintelligible speech and incapacitating nasal regurgitation, requiring pharyngoplasty. Indeed, undiagnosed submucous cleft palate has been found to account for up to 30% of post adenoidectomy VPI (Croft et al 1981, Donnelly 1994).

While overt palatal clefts are easily recognised, submucous cleft palates (SMCP), which are more common in VCFS, are far less obvious or may be occult. Our detection and understanding of SMCPs are improving as the use of flexible nasedoscopy becomes more widespread. The cardinal signs of an overt SMCP include a bifid uvula, notched posterior border of the hard palate, absent muscularis uvulae (on flexible nasendoscopy) and audible hypernasality with visible nasal emissions (Table 8). A bifid uvula may be associated with SMCP but has been found in 0.2%-1.8% of general paediatric populations (Finglestein et al 1993). Notching of the posterior border of the hard palate is often difficult to feel in the young infant. In the normal child a prominent midline palatal spine is felt. Absence of this spine may indicate that a notch is present but it may not be possible to confirm this by palpation until after 6-12 months of age. Flexible nasendoscopy is required in order to detect an absence of the muscularis uvulae. It may be associated with a visible zona pellucida (the nasendoscope produces a mid-line shaft of light through the palate which is seen in the mouth, due to absence of the muscularis uvulae). An 'occult' SMCP implies no oral signs including no bifid uvula and no notch. However the absence of the muscularis uvulae is detectable with nasendoscopy. This may be made more obvious, in the older child, by observing the dorsum of the palate as they suck forcefully through a narrow straw. A trough is seen in the mid-line instead of the tensing fibres of the normal muscularis uvulae (Finklestein et al 1996).

Audible hypernasality is emphasised when the patient uses fricatives (eg. f / s / v / z), plosives (eg. b / d / g / k / p / t) and affirmatives (eg. ch / ge). Visible nasal emissions during speech, which fog a metal tongue depressor held under the nares, are further evidence of velopharyngeal air escape. A speech pathologist can readily quantify emissions using a nasometer which objectifies diagnosis and response to therapy. A more subtle sign of palatal dysfunction is abnormal movement of the soft palate with phonation. Normally the curve of the tensed palate resembles a Gothic arch. Tenting with lateral dimpling, due to separation of the levator palatini 'lift points', ought to raise suspicion of an anomaly of muscle insertion (Finklestein et al 1992).

VCFS is the most common syndrome associated with clefts of the secondary palate, especially SMCP, accounting for 5-8% of all cleft cases (Shprintzen et al 1985, Lipson et al 1991, Finklestein et al 1992, Goldberg et al 1993). In a series of 246 patients with VPI, 9.3% were found to have VCFS (Witzel et al 1989). It is therefore not only important in every pre-adenoidectomy assessment to exclude a palate anomaly but, should VPI be detected in any child, VCFS should be considered as a primary diagnosis and the other phenotypic features sought out.

Other phenotypic characteristics are of particular relevance to the otolaryngologist. VCFS patients tend to have small, simple, low set ears sometimes with narrow external canals and preauricular clefts. Associated sensorineural hearing loss (SNHL) has been reported (Shprintzen et al 1978) and should always be excluded with audiometry. Conductive hearing loss (CHL) is more common, occurring in up to 77% of cases (Shprintzen et al 1981). It is usually due to Eustachian tube dysfunction and is, particularly, a feature in patients with palatal abnormalities. In our cohort, one patient had SNHL and 62% of patients had persistent middle ear effusions requiring insertion of ventilation tubes.

VCFS patients are prone to recurrent respiratory tract infections, otitis media and sinusitis. This may include recurrent adenotonsillitis. In contrast, lymphoid hypoplasia, sometimes with an absence of tonsil and adenoid tissue, has been reported, although it was not seen in our patients. Most commonly, the VCFS patient will be referred to the otolaryngologist because of speech problems associated with velopharyngeal insufficiency. Analysis of our cohort demonstrated an 88% incidence of VPI in the VCFS patients, with 35% having a palatal cleft. Before contemplating tonsillectomy or pharyngoplasty in these patients it is important to observe the pharynx for abnormal pulsation which may indicate medially placed, tortuous internal carotid arteries. Aberrant, medially placed carotid arteries in the pharynx and post nasal space have been reported in up to 25% of VCFS patients (Goldberg 1993). In some cases this has prevented adequate pharyngoplasty and a prosthetic speech appliance has been required (MacKenzie-Stepner et al 1987, Ross et al 1996). An otolaryngologist suspecting a patient to have VCFS should not only ensure adequate treatment of VPI, hearing loss and exacerbations of infection but also organise appropriate investigations and referral to confirm the diagnosis.

Due to the wide range of associated anomalies and the variability of clinical severity, there is phenotypic overlap between VCFS, di George syndrome, CHARGE and Pierre-Robin sequence (Goldberg et al 1993). The predominance of palatal dysfunction, cardiac anomalies and the described facial features in combination with cytogenetic confirmation of the chromosome 22q11.2 deletion are most suggestive of a diagnosis of VCFS. The genotypic characteristic of VCFS, a deletion in the long arm of chromosome 22 at 22q11.2, is detected in up to 80% of VCFS patients (Driscoll et al 1993). Recent developments in cytogenetics have enabled an assay to be performed in order to detect the specific chromosome 22q11.2 deletion using Fluorescent In Situ Hybridisation (FISH) analysis in patients presenting with this phenotype. It is hypothesised that the deletion results in a gene imbalance that affects the migration of neural crest cells into the branchial arches and outflow septum of the heart during foetal development, producing the phenotypic features (Ryan et al 1997). Whereas familial transmission of a microdeletion syndrome is uncommon, 22q11.2 deletion is reported to be inherited in 10-28% of cases (Dallapiccola et al 1996, Leana-Cox et al 1996, Ryan et al 1997). Thirty eight percent in our series had affected relatives. It is controversial whether there is a parental sex bias, but maternal transmission is thought to be more prevalent (Desmaze et al 1993). In our study, there was a tendency for maternal carriage of the deletion (15%) and expression of phenotypic features (23%) agreeing with previous work that suggested that carrier parents are more mildly affected than the proband (patient) (Wilson et al 1993, Leana-Cox et al 1996).

Patients with an identified deletion in one arm of their chromosome 22 have a 50% risk of transmission to their offspring and should therefore be offered genetic counselling. Prenatal ultrasound is a poor modality to detect VCFS in at-risk foetuses due to the variability of phenotypic expression. For both diagnostic and genetic counselling purposes, the FISH test provides the most efficient and accurate diagnostic assay. This sensitive and rapid test utilises a cosmid containing DNA specific to the Di George Critical Region on the long arm of chromosome 22. Diagnosis by FISH simply requires a blood sample from the patient. For prenatal assessment it may be used with chorionic villous sampling within the first trimester (Driscoll et al 1993).

Conclusion

Children with VCFS often present to an otolaryngologist due to their predisposition for otitis media, recurrent infections and speech difficulties. However, palatal dysfunction or clefting of the secondary palate, of which VCFS is the most common cause, may not always be apparent. As demonstrated by our cohort, a diagnosis of VCFS ought to be contemplated in children with historical features such as growth, developmental and speech delay, congenital cardiac anomalies, feeding problems during infancy and nasal regurgitation. It should be considered in those with a family history of cleft palate or cardiac disorders, especially if associated with short stature and learning difficulties. Every patient in whom adenoidectomy is contemplated should be examined for speech anomalies, palatal dysfunction and the facial features of VCFS. An understanding of other clinical features and phenotypic traits enables the clinician to detect those patients in whom adenoidectomy may lead to disabling velopharyngeal insufficiency. Cognisance of the associated audiological, cardiac and developmental sequelae of this syndrome ensures appropriate investigation, referral and genetic assessment.

References

CROFF C.B., SHPRINTZEN R.J., RUBEN R.L. (1981) Hypernasal speech following adenotonsillectomy. Otolaryngol. Head Neck Surg. 89,179-188.

DALLAPICOLA B., PIZZUTI A., NOVELLI G. (1996) How many breaks do we need to CATCH on 22ql 1? Am. J. Hum. Genet. 59,7-11.

DESMAZE C., PRIEUR M., AMBLARD F. ET AL (1993) Physical mapping by FISH of the Di George critical region (DGCR): Involvement of the region in familial cases. Am. J. Hum. Genet. 53, 1239-1249.

DONNELLY M.J. (1994) Hypernasality following adenoid removal. Ir. J. Med. Sci. 163, 225-227.

DRISCOLL D.A., SALVIN J., SELLINGER B., BUDARF M.L. ET AL (1993) Prevalence of 22qll microdeletions in Di George and velocardiofacial syndromes: Implications for genetic counselling and prenatal diagnosis. J. Med Genet. 30, 813-817.

FINKLESTEIN Y., TALMI Y.P., KRAVITZ K., BAR-ZIV J. ET AL (1991) Study of the normal and insufficient velopharyngeal valve by the "forced sucking test". Laryngoscope 101, 1203-1212. FINKLESTEIN Y., TALMI Y.P., NACHMANI A., HAUBEN D.J., ZOHAR Y. (1992) Occult and overt submucous cleft palate: From peroral examination to nasendoscopy and back again. Int. J. Pediatr. Otorhinolaryngol. 23,25-34.

FINKLESTEIN Y., ZOHAR Y., NACHMANI A., TALMI Y.P. ET AL (1993) The otolaryngologist and the patient with velocardiofacial syndrome. Arch. OtolaryngoL Head Neck Surg. 119, 563-569. GOLDBERG R., MOTZKIN B., MARION R., SCAMBLER P.J., SHPRINTZEN R.J. (1993) Velocardiofacial syndrome: A review of 120 patients. Am. J. Med. Genet. 45, 313-319.

KOK L.L., SOLMAN R.T. (1995) Velocardiofacial syndrome: Learning difficulties and intervention. J. Med. Genet. 32, 612-8. LEANA-COX J., PANGKANON S., EANET K.R., CURTIN M.S., WULFSBERG E.A. (1996) Familial Di George I velocardiofacial syndrome with deletions of chromosome area 22qll.2: report of five families with a review of the literature. Am. J. Med. Genet. 65, 309-316. LIPSON A., YUILLE D., ANGEL M., THOMPSON P.G., VANDERVOOD J.G., BECKENHAM E.J. (1991) Velocardiofacial (Shprintzen) syndrome: An important syndrome for the dysmorphologist to recognise. J. Med. Genet. 28, 596-604. MACKENZIE-STEPNER K., STRINGER D.A., LINDSAY WK., MUNRO I.R. (1987) Abnormal carotid arteries in the velocardiofacial syndrome: A report of three cases. Plast. Reconstr. Surg. 80, 347-351. ROSS D.A., WITZEL M.A., ARMSTRONG D.C., THOMSON H.G. (1996) Is pharyngoplasty a risk in velocardiofacial syndrome? An assessment of medially displaced carotid arteries. Plast. Reconstr. Surg. 98, 1182-90.

RYAN A.K., GOODSHIP J.A., WILSON D.I. ET AL (1997) Spectrum of clinical features associated with interstitial chromosome 22ql I deletions: A European collaborative study, J Med Genet. 34,798-804. SHPRINTZEN RJ., GOLDBERG R.B., LEWIN M.L. ET AL (1978) A new syndrome involving cleft palate, cardiac anomalies, typical facies and learning disabilities: velocardio-facial syndrome. Cleft Palate J. 5, 56-62.

SHPRINTZEN R.J., GOLDBERG R.B., YOUNG D., WOLFORD L. (1981) The velocardiofacial syndrome: A clinical and genetic analysis. Pediatrics 67, 167-172.

SHPRINTZEN R.J., SIEGEL-SADEWITZ V.L., AMARTO J., GOLDBERG R.B. (1985) Anomalies associated with cleft lip, cleft palate or both. Am. J. Med. Genet. 20, 585-595.

WILSON D.I., BURNS J., SCRAMBLER P., GOODSHIP J. (1993) Di George syndrome: Part of CATCH 22. J. Med Genet. 30, 852-856. WITZEL M.A., POSNIK J.C. (1989) Patterns and location of velopharyngeal valving problems: Atypical findings on video nasopharyngoscopy. Cleft Palate J. 26, 63-67.

WULFSBERG E.A., LEANA-COX J., NERI G. (1996) What's in a name? Chromosome 22q abnormalities and the Di George, velocardiofacial and conotruncal anomalies face syndromes. Am. J. Med Genet. 65, 317-319.

DAVID LOWINGER, PAUL WALKER AND MATTHEW EDWARDS

John Hunter Children's Hospital

Newcastle, New South Wales

David Lowinger M.B., B.S.

Registrar, Otolaryngology, Head and Neck Surgery John Hunter Hospital

Paul Walker F.R.A.C.S.

Consultant Paediatric Otolaryngologist John Hunter Children's Hospital Matthew Edwards M.D., F.R.A.C.P. Clinical Geneticist - Hunter Genetics Correspondence:

Dr David Lowinger

Registrar, Otolaryngology, Head and Neck Surgery 12/50-52 Beach Road, Bondi Beach 2026

Fax: 02 9371 6419

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