Chromosome 22q11.2 deletion syndrome: an underestimated cause of neuropsychiatric impairment in adolescence

Abstract

Sirs: Chromosome 22q11.2 deletion syndrome is a common multiple malformation syndrome estimated to affect between 1 in 4000 and 1 in 5000 individuals [1]. With the advent of molecular genetics a 3-Mb microdeletion within 22q11 was found to underlie a heterogeneous group of disorders with overlapping features, such as Di George and velocardiofacial syndrome [2, 3]. The phenotype of the disorder has expanded considerably within the last few years, whereas the clinical features vary significantly among affected individuals [4]. However, cardiovascular defects, immunological deficits, neurodevelopmental retardation, craniofacial abnormalities and hypocalcemia are recognised as the major and most frequent manifestations of the syndrome [5]. A 17-year-old boy presented with a gradual cognitive and behavioral decline over the last 18 months. The symptom onset coincided with a febrile gastrointestinal tract infection and was initially characterized by anxiety, altered sleep pattern, bizarre statements and actions and lack of initiative. The patient exhibited bland, and at times inappropriate affect, whereas his thought and behavior were mildly but progressively disorganised. The patient became eventually socially withdrawn and was unable to attend to his school activities. However, no hallucinations or delusions were present. He showed poor response to neuroleptic medication and remained withdrawn with psychomotor retardation and poverty of speech. His past medical history was significant for non-febrile neonatal seizures, which were attributed to hypocalcemia. At that time, he was diagnosed as having hypoparathyroidism, whereas further investigation showed thymic hypoplasia with marginally reduced T-cell numbers. However, no chromosomal abnormality was found on karyotyping. Developmental milestones were also delayed; he began to walk at 17 months and first combined single words into full sentences around 48 months of age. The patient had attended regular school classes, but his overall school performance had always been poor with prominent deficits in visuo-spatial abilities and executive functioning. He was also diagnosed as having bilateral stenosis of the external auditory canal, and an inguinal hernia had been repaired at 3 months of age. Moreover, the patient had an episode of septicemia due to pneumococcal infection at the age of 13. His family history was unremarkable, apart from a diagnosis of schizophrenia in a paternal great uncle. The patient was admitted and evaluated mainly by the neurology services. On examination, he was noted to have slightly dysmorphic facial features consisting of broad nasal root, malar flattening and relative retrognathia. His speech was hypernasal without overt cleft palate, but the general neurological and physical examination were otherwise unremarkable. Neuropsychological assessment revealed moderate deficits on verbal, as well as non-verbal reasoning tests, whereas the patient’s visual perceptual skills and memory appeared to be mildly impaired. The prominent difficulty of the patient in sustaining concentration exaggerated his deficits, but his overall neuropsychological profile was consistent with significant cerebral dysfunction. Routine hematology showed mild thrombocytopenia, increased free thyroxin values and marginally decreased calcium levels. Routine EEGs revealed on one occasion brief bursts of generalised epileptiform activity; however, successive EEGs as well as video-EEG monitoring failed to detect any abnormality. MRI of the brain using volumetric acquisition as well as echocardiogram proved normal. The patient was then extensively investigated in a tertiary university centre in order to exclude an underlying neurological disorder. Blood films for acanthocytes, serum copper and ceruloplasmin, slit lamp examination, antibasalganglia antibodies, white cell enzymes as well as very long chain fatty acids, plasma amino acids and urine organic acids were either normal or negative. The suspicious EEG findings led to skin biopsy for Lafora disease, which revealed no abnormality. Subsequently, a muscle biopsy was undertaken which provided no evidence for a mitochondrial encephalomyopathy. Finally, on readmission 2 years later a fluorescence in-situ hybridization (FISH) using the N25 probe was performed, which demonstrated a microdeletion within chromosome 22q11.2. It is well established that individuals with chromosome 22q11.2 deletion syndrome are at risk to develop a range of psychiatric illnesses. Early reports cite a high prevalence of psychotic disorders, specifically schizophrenia, among adults carrying the deletion and LETTER TO THE EDITORS