Patients

A total of 551 patients were investigated for the presence of a 22q11 deletion over a seven year period (1992–8). Most diagnostic FISH tests (66%) were requested by a clinical geneticist, in nearly one third of cases the investigation was requested by a paediatrician, and the remaining requests were made by a paediatric pathologist after postmortem examination.

Results

Deletions at 22q11.2 were detected in 67 of the 551 patients tested. Notably, only 12% of these deletions were visible by conventional cytogenetic banding studies. The clinical scenarios in which these individuals presented are shown in table 1.

Information regarding the various systems involved was not available for all 67 patients. Details regarding cardiac status were known for 55, facial appearance for 58, palate for 41, development for 43, thymus gland for 34, and serum calcium for 39 patients. Cardiac defects were detected in 46 patients, including ventricular septum defect (26 patients), Fallot's tetralogy (10), atrial septum defect (eight), and interrupted aortic arch (seven). Dysmorphic facies (unusually shaped ears, long nose with broad bridge, microstomia, micrognathia and upslanting, short palpebral fissures) were noted in 50 patients. Thymic hypoplasia or aplasia was detected in 16 individuals and hypocalcaemia was documented in 21. Abnormalities of the palate (such as cleft, slack, or high palate) were seen in 24 patients, and learning difficulties or developmental delay were noted in 32. The observation of long or tapering fingers was specifically recorded in 13 of the 67 patients.

Of the 40 affected children whose parents had been tested, nine were found to have inherited the deleted chromosome, usually from the mother (eight patients).

Discussion

In our series, patients had similar frequencies of congenital heart disease, hypocalcaemia, and palatal abnormalities to those reported in two recent studies,4 5 but we discovered that the main diagnostic problem is pronounced clinical variability, which causes the true diagnosis to be overlooked or delayed considerably.

Retrospective examination of our clinical data revealed useful guidelines for prospective clinical diagnosis (table 2) that should permit the diagnosis of the condition in most individuals. We suggest that FISH 22 deletion analysis should be performed on patients who meet one of the criteria in column A. Thus, any patient with a conotruncal congenital cardiac anomaly, even in isolation, should be investigated for the presence of the deletion, because this problem occurs so frequently in 22q11 deleted individuals,4 and can be the only manifestation.6 Alternatively, the possession or history of two features in column B, or one feature in column B in addition to one in column C, are regarded as sufficient to merit investigation. These guidelines were devised with the aim of achieving a high sensitivity in the initial detection of patients for whom the FISH analysis should be considered. Retrospectively, the use of table 2alone would have permitted the detection of our 67 patients with deletions with 100% sensitivity, but the available data do not permit an accurate determination of the specificity or positive predictive value of the guidelines.

Typical presenting features are also determined by the age of the individual. In the perinatal period, the presence of any cardiac or palatal anomaly or of hypocalcaemia should prompt close examination for other dysmorphic features. In childhood, suspicious findings are velopharyngeal insufficiency (perhaps indicated by hypernasal speech or recurrent otitis media), myopathic looking facies (fig 1), short stature, and mild learning difficulties. In adults, however, clues to diagnosis are often more subtle, including hypernasal speech, psychiatric symptoms, mildly dysmorphic facies, and long slender fingers, but close examination of the childhood medical and educational histories nearly always pays dividends.

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Figure 1

Typical myopathic facial appearance in a boy with a chromosome 22q11 deletion. (Photograph reproduced with permission of the patient's parents.)

To summarise, the diagnosis in a large proportion of our patients was delayed either because there was no pathognomonic clinical feature or there was erroneous clinical diagnosis of an unprovable rare condition (table 1). Chromosome 22q11 deletion is a relatively common condition and is a readily diagnosed cause of serious congenital malformations and puzzling dysmorphic syndromes.