From the Division of Pediatric Neurology, Department of Pediatrics, Advanced Peditric Center, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India.
Reprint requests: Dr. Pratibha D. Singhi, Additional Professor, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India.

Manuscript Received: April 13, 1999;
Initial review completed: May 18, 1999;
Revision Accepted: August 30, 1999

Velocardiofacial syndrome (VCFS) is a genetic disorder with an estimated frequency of 1 in 4000 live births(1). This disorder is characterized by cardiac defects, cleft palate, learning disabilities and mild facial dysmor-phology(2). The identification of these patients is difficult because it is a multisystem syndrome with numerous anomalies, many of which are considered minor and found in general population(3). The enormous variability of this condition is seen by the different clinical features which are present in the affected members of the same family(4,5). There is a paucity of documentation on this subject in Indian literature. Hence we report a pair of siblings born to nonconsanguineous parents who had variable clinical phenotype.

Case 1: A 7½-year-old boy was referred for evaluation of developmental delay and abnor-mal behavior. He was delivered normally at term with an uneventful perinatal period. He had cleft palate which was repaired at 4 years of age. He had delay in acquiring milestones in all sectors. The parents reported poor scholastic performance as well as hypernasality of speech since he started verbalizing. He had frequent chest infections and was diagnosed to have a ventricular septal defect at 1 year of age.

On physical examination the patient was short statured, [height - 115.6 cm (93% of median)] and had microcephaly [head circumference 44.3 cm (<3 SD)]. He had a long face with prominent nasal bridge and a broad tip of the nose. He had flat maxillae, microg-nathia and retruded mandible with a repaired cleft palate. The child had an everted upper lip with short philtrum. The ears were prominent and symmetric (Fig. 1). He had typical slender hands with tapering fingers which were hyperextensible (Fig. 2).

On evaluation of intelligence, his IQ was 32. Social quotient assessment by VSMS scale was 38.6. On developmental profile, his academic age was 2 years 4 months and his social age was 3 years 6 months. His behavior pattern was preservative, stereotypic, and not goal directed.

Chest X-ray revealed cardiomegaly and echocardiography showed a small perimem-branous ventricular septal defect. His bone age was normal; computed tomography scan of brain and ultrasound abdomen for kidneys did not reveal any structural defects. Ophthalmo-logical assessment and audiometry was normal.

Fig. 1. Typical facial findings in Case 1 with velocardiofacial syndrome.	Fig. 2. Hands of Case 1 showing spindle shaped and tapering fingers.

Case 2: This 1½-year-old male was the younger brother of Case 1. He was delivered full term of an uneventful pregnancy and had no birth asphyxia. The child had feeding difficulties and failure to thrive since birth. There was history of nasal regurgitation of milk and he also had a cleft palate which was repaired at 1 year of age. He had developmental delay in all sectors. The parents complained that the child was floppy since birth and also had constipation.

On examination he had dysmorphic features. His length was 72 cm (90% of median) and head circumference was 42.5 cm (<3 SD). He had narrow palpebral fissures, maxillary deficiency, microsomia, small chin and a large fleshy nose, a broad nasal bridge with asymmetric prominent auricles (Figs. 3 & 4). Cardiovascular examination was normal. Neurological assessment revealed gross motor and fine motor and language delay. The child was hypotonic but reflexes were normally elicitable.

On investigation the echocardiography, CT scan head, bone age, thyroid profile, serum calcium and ultrasound abdomen were within normal limits.

Both the children were diagnosed as cases of velocardiofacial syndrome and they were provided rehabilitation particularly speech therapy and special education. The parents were examined in details and were not found to have any features of the syndrome. The grandparents could not be contacted.

The parents were informed about the variable penetrance and manifestations of the syndrome and its associated problems. They were advised to get chromosomal anlaysis including FISH analysis and to bring the children for periodic follow up.

VCFS was initially described by Sphrintzen et al. in 1978 as a multiple malformation syndrome that included clefting of palate, cardiac anomalies, a characteristic facial phenotype and learning disability(6). Since then more than 40 physical anomalies including hypocalcemia, hypotonia, mental retardation, thrombocytopenia, blood vessel anomalies such as tortuous retinal vessels have been described(7). A newly recognized finding is the presence of psychiatric disorder in these patients(8).

The typical patient with VCFS presents with a cluster of velar, cardiac, facial, digital and mental findings. All these features were amply demonstrated in Case 1. The characteristic facial features found in these cases are a long vertical face, large fleshy nose, narrow alar base, flattened malar region, narrow palpebral fissures, retrognathia, small downturned mouth and prominent ears(6). Both the children had characteristic facies and were also short statured as is found in 30% of cases(2). A small head circumference which was present in both the cases is a common finding. Recently, structural brain defects have been described(9) but they were not present in either of the cases.

The oral manifestations consist of clefts of the secondary palate and velopharyngeal insufficiency(10). Both the brothers had cleft palate which were repaired. The elder sib had hypernasality of speech, which was probably due to velopharyngeal insufficiency. The history of feeding difficulties, failure to thrive and nasal regurgitation of milk in the younger boy could also be explained by the presence of the oral manifestations.

These children commonly have motor incoordination and poor development of numerical concepts. These along with poor abstract reasoning leads to increasingly poor psychological, language and academic performance(9). Personality may tend towards preservative stereotypic behavior as was seen in Case 1.

The problems with which such children generally present in infancy were all seen in Case 2, i.e., hypotonia, development delay, constipation and failure to thrive.

Not all principal features are present in each case; particularly cardiac disease is not an essential feature. The elder sib had VSD but the younger sib did not. The younger sib also did not have typical digital findings like spindle shaped slender fingers. Frequent upper respira-tory tract infections, pneumonia or bronchitis are common in VCFS as were reported only in the elder sib(9). Studies on monozygotic twins and affected members of the same family who have different clinical features show the enor-mous variability seen in this conditions(4,5).

In 1993 the New Castle and Tyne group suggested the acronym CATCH22 as an alternative name for this syndrome [C = cardiac anomalies, A = abnormal facies, T = thymic hypoplasia, C = cleft palate, H = hypocalcemia, 22 = affected chromosome](11). Both hypocalcemia and thymic hypoplasia were absent in both the cases. Hypothyroidism which has also been described as an associated finding was absent in these sibs(7). Conductive hearing loss caused by chronic otitis media found in 77% of the typical cases was not found in either of the sibs(12).

The identification of this disorder is dificult because it is a multisystem syndrome with numerous anomalies. There is no clinical find-ing which is pathognomonic for diagnosis of VCFS nor is there a composite of major and minor criteria that can be used to make a definitive diagnosis(3). Therefore it is important to consider the diagnosis in any patient with more than one of the clinical findings characteristic of this syndrome.

As more is learned and new clinical findings are uncovered in patients with VCFS, the spectrum of affected patients encompasses many patients previously described as having DiGeorge syndrome (DGS), Pierre Robin Sequences (PRS) and the CHARGE associa-tion. Both our cased did not have hypocalcemia, thymic aplasia, short philtrum of lip and anti-mongoloid slant of eyes which are characteristic of DGS. The pair of brothers did not have glossoptosis which is one of the three features like cleft palate and micrognathia which are found in PRS. On the contrary many other facial features, cardiac findings and skeletal changes characteristic of VCFS were found in them. These children did not fit into CHARGE association as there was absence of coloboma in the eyes, choanal atresia, genital hypoplasia and deafness.

Most cases of VCFS are sporadic, but when inherited, it has an autosomal dominant pattern of transmission with variable penetrance. It results from a deletion of 22 q 11.2(13). High resolution Karyotyping and DNA analysis which is required to pick up the genetic make up of these cases is advisable.

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