Left, Eight-month-old boy with velocardiofacial syndrome manifesting typical facial characteristics including hooded eyelids, hypoplastic nasal alae, malar flatness, and crumpled/protuberant auricles. Right, Healing scars in preauricular and submandibular regions are secondary to mandibular distraction procedure.
Six-week-old boy with velocardiofacial syndrome manifesting complete cleft of lip and palate, auricular malformation, and mandibulomaxillary hypoplasia.
Left auricle of 6-week-old infant with velocardiofacial syndrome.
Duke SG, McGuirt, WF, Jewett T, Fasano MB. Velocardiofacial SyndromeIncidence of Immune Cytopenias. Arch Otolaryngol Head Neck Surg. 2000;126(9):1141-1145. doi:10.1001/archotol.126.9.1141
Velocardiofacial syndrome (VCFS) is associated with a broad clinical spectrum that frequently overlaps the DiGeorge syndrome. Both have been linked to chromosomal microdeletions of chromosome 22 (22q11.2). DiGeorge syndrome is associated with T-cell dysfunction. What is the incidence of immune cytopenias in children with VCFS?
To (1) identify, (2) characterize, (3) quantify, and (4) follow up the immunologic deficits in children initially seen in our institution with VCFS.
Prospective clinical evaluation of patients with the features of VCFS.
Twenty consecutive children with the clinical diagnoses of VCFS.
Tertiary care children's hospital.
Main Outcome Measures
All 20 children had genetics evaluation with chromosomal analysis. Immunologic evaluations included serum immunoglobulin concentrations, lymphocyte studies, and mitogen and antigen stimulation studies.
Five (25%) of 20 children were noted to have T-cell dysfunction with a clinical presentation marked by recurrent upper respiratory tract infections. Three of these 5 children had resolution of the T-cell dysfunction over a 2-year period. The 2 children with persistent cytopenias combined with immunoglobulin dysfunction required intravenous IgG infusions to control their infections.
Velocardiofacial syndrome is associated with an increased incidence of immune cytopenias and, thus, warrants evaluation in any child with the clinical diagnosis of VCFS. This immune deficit may be transient and depends on the age of the evaluation of the child.
IN 1978 SHPRINTZEN et al1 first described the velocardiofacial syndrome (VCFS) in 12 children with similar presentations of cleft palate, cardiac anomalies, typical facies, and learning disbilities. Since then, several hundred patients have been identified with VCFS. Dominant clinical features of VCFS include overt or submucous clefting of the secondary palate, velopharyngeal insufficiency, auricular abnormalities, lymphoid hypoplasia, ventriculoseptal defect, psychiatric disturbance, and learning disability.2 Sedlánocodeková as cited by Vrtinocodeka et al3 observed a similar pattern of velar hypoplasia or submucous clefting accompanied by hypernasal speech, facial dysmorphisms, pointed digits, cardiac malformations, and mental retardation in 48 children of Eastern European origin and named it "velofacial hypoplasia."
Velocardiofacial syndrome is an autosomal dominant disorder that has been cytogenetically linked to chromosome 22. Fluorescence in situ hybridization studies identified microdeletions of 22q11.2 in patients with VCFS.4 Recent work by Vrtinocodeka et al3 have identified the 22q11.2 microdeletion in 8 of 11 patients with velofacial hypoplasia (Sedlánocodeková syndrome). This deletion may also be present in patients with DiGeorge syndrome (DGS), conotruncal anomaly face syndrome, Caylor cardiofacial syndrome, Opitz syndrome, and some cases of isolated conotruncal cardiac anomalies5,6 suggesting that these may represent a spectrum of abnormalities associated with 22q11.2 microdeletions.7 DiGeorge syndrome can occur as a component of VCFS8 with significant overlap in the clinical features. DiGeorge syndrome results from a defect of the third and fourth pharyngeal pouches leading to thymic and parathyroid aplasia and conotruncal heart defects. These patients also manifest severe T-cell deficiency.
Recently, Depiero et al9 reported recurrent immune cytopenias in 2 patients with DGS\VCFS manifested as autoimmune hemolytic anemia and immune thrombocytopenia. McDonald-McGinn et al7 have recommended evaluation of the immune system in those patients identified with the 22q11.2 deletion. This study examines the incidence of immune cytopenias in children with VCFS. The objectives of the study were to (1) identify, (2) characterize, (3) quantify, and (4) follow up on the immunologic deficits in children initially seen in our institution who had VCFS.
From February 1995 through November 1997, 20 children were identified with VCFS by the senior geneticist (T.J.) based on clinical presentation (Figure 1, Figure 2, Figure 3, and Table 1) and subsequent cytogenetic evaluation for the 22q11.2 deletion. The microdeletion was confirmed by fluorescence in situ hybridization analysis. The children were followed up prospectively by two of us (W.F.M. and T.J.). A multidisciplinary evaluation including genetics, otolaryngology, plastic surgery, immunology, cardiology, speech pathology, audiology, dental, and developmental pediatrics was obtained.
Immunologic evaluation was undertaken at the time of enrollment in the study in all children older than 1 year. Children who were identified with VCFS but were younger than 1 year did not undergo immunologic evaluations until after reaching 1 year of age. Immune assessment included complete blood cell count, T- and B-cell enumeration studies, lymphocyte activation studies, and serum immunoglobulin concentrations. In the children with immunologic defects, studies of immune function were repeated at 6-month intervals.
The mean age at time of diagnosis was 18.7 months (age range, 6-37 months). The study group consisted of 17 whites (85%) compared with 3 African Americans (15%). There were 15 male compared with 5 female subjects. Eight children (40%) manifested immunodeficiency: 5 children (25%) had impaired T-cell production, 2 (10%) had impaired T-cell function, and 5 (25%) had humoral defects (Table 2). In the 8 children with immunologic defects, studies of immune function were repeated at 6-month intervals until completion of the study. In 3 of the 5 children with T-cell immunologic impairments, the defects were noted to be mild and resolved on an average of 16 months. The 2 children with persistent T-cell defects were found to have both impaired T-cell production and function as well as fluctuating immunoglobulin dysfunction. These children responded to immunoglobulin infusion during periods of marked immunoglobulin dysfunction.
The clinical presentation of the children with immunologic defects was characterized by a higher incidence of upper respiratory tract infections. All 5 children with T-cell immunologic defects had repeated bouts with bronchiolitis. The 2 children with persistent defects required frequent hospitalizations. Otitis media occurred with 1.5 times greater incidence in the 8 children with immunologic defects. All 8 children with immunologic defects required the insertion of tympanostomy tubes compared with 8 of the 12 immunocompetent children.
The etiology of DGS is considered heterogenous with multiple chromosomal abnormalities resulting in the syndrome. However, recent cytogenetic and molecular studies have demonstrated that a chromosome 22q11.2 deletion is the cause of DGS in most cases.10 Initial support for this came with the identification that loss of this locus through unbalanced translocation with loss of the short arm and proximal long arm of chromosome 22 or interstitial deletion in the region resulted in DGS.7 Subsequent molecular studies of cytogenetically normal DGS patients demonstrated microdeletions of 22q11.2 in approximately 90% of samples.10
Goldberg et al2 demonstrated that cytogenic analyses using high-resolution banding techniques identified interstitial deletions of 22q11.2 in 20% of patients with VCFS. This in tandem with features common between DGS and VCFS suggests the 2 share a common pathogenesis. Subsequent molecular studies with chromosome 22 probes identical to those used to identify patients with DGS have identified submicroscopic deletions of 22q11.2 in most patients with VCFS. McDonald-McGinn et al7 propose that VCFS and DGS may represent variant manifestations of a single disorder, the 22q11.2 deletion syndrome. The development of fluorescence in situ hybridization techniques in the early 1990s has refined the analysis of patients with VCFS and DGS. Subsequent use of flourescence in situ hybridization analysis has identified microdeletions of the same sequence in most patients with VCFS, DGS, Opitz syndrome, conotruncal anomaly face syndrome, Caylor cardiofacial syndrome, and some cases of isolated conotruncal cardiac anomalies supporting the theory that these may represent a phenotypic spectrum of a genotypic anomaly. Identification of a deleted region of chromosome 10 in some patients with VCFS/DGS may explain the subset of these patients, who do not exhibit the 22q11.2 microdeletion.11
DiGeorge sequence results from a failure of development of the third and fourth pharyngeal pouches resulting in thymic and parathyroid hypoplasia or aplasia. The resultant syndrome is characterized by hypocalcemia and T-cell immunologic deficits. Immunologic deficits in VCFS have only recently been described.9 We attempted to further study the immune system of children identified at our institution with VCFS. In our experience, T-cell immunologic impairments increased the risk of pulmonary and upper respiratory tract infections. Causative organisms were not significantly different from the normal population.
The incidence of immune cytopenias in the study cohort was 8 children (40%) with only 2 (10%) demonstrating persistent deficiencies. These 2 children represented the most severe immune defects and more frequent and severe infectious illnesses. These children also exhibited more overt clinical features including cleft palate, cardiac anomalies, and auricular malformation. The remainder of the study cohort manifested more subtle clinical features of VCFS. This finding suggests that immune cytopenias may exhibit a spectrum of phenotypic variability similar to other clinical features.
The incidence of otitis media in our study cohort was 1.5 times greater in the 8 children with immune defects. This is echoed in an increased frequency of tymanostomy tube insertion (100% vs 75%). The cause of this increase, however, cannot be solely attributed to immunologic factors. The incidence of chronic otitis media with effusion is well known to be higher in children with cleft palate.
The finding of immunocompromise in 8 (40%) of the 20 children in our study is less than the 77% identified by McDonald-McGinn et al7 in a review of 181 patients with the 22q11.2 deletion. Their study examined all patients with the chromosome 22 deletion, including DGS and other more severe syndromes. If the degree of immune dysfunction is directly related to the severity of the 22q11.2 syndrome, then the limitation of the study group to patients with VCFS would be expected to yield a lower incidence of immune cytopenias. Further, the children in our study were not investigated for immunologic status until after their first birthday. Normative data for quantitative immunoglobulin and T-cell levels are not definitive in children younger than 12 months. Given that the T-cell impairments in 3 of 5 children resolved during the 2-year study, it is possible that subtle immune deficiencies may have resolved prior to 12 months of age.
A longitudinal study of patients is needed to further elucidate the nature of the immune defects. Such a study could detect intermittent immune dysfunction and better quantify the role such deficiency plays in the infectious illnesses suffered by these patients. Increased patient numbers are needed to allow for multivariate analysis of confounding variables such as the presence or absence of overt cleft palate. Until such data are available, clinicians should maintain a low threshold for obtaining immune function analysis of patients identified with VCFS. Patients with VCFS and their families should avoid live vaccines and receive only irradiated, cytomegalovirus–negative blood products. Bactrim prophylaxis may have a role for patients with recurrent infections. Those patients with severe immunodeficiency may also benefit from gammaglobulin transfusion (400 mg/kg per dose every 3-4 weeks) as did 2 of the patients in our study.
Accepted for publication February 22, 2000.
Presented at the American Society of Pediatric Otolaryngology, Palm Beach, Fla, May 12, 1998.
Corresponding author: William F. McGuirt, Jr, MD, Department of Otolaryngology, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157.