Short report
Diagnosis of distal 22q11.2 deletion syndrome in a patient with a teratoid/rhabdoid tumour

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Abstract

We report an 18 year old patient with mild intellectual disability who was diagnosed with a late onset teratoid/rhabdoid tumour by histological and immunohistochemical studies. Array-CGH studies, performed on a peripheral blood sample, showed a 3.4 Mb deletion of chromosome 22q11.2, distal to the common DiGeorge syndrome (DGS) or Velocardiofacial syndrome (VCFs) region. This deletion is consistent with a diagnosis of distal 22q11.2 deletion syndrome. The deletion encompasses the INI1/SMARCB1 tumour suppressor gene. Biallelic inactivation of this gene is characteristic of atypical teratoid/rhabdoid tumours.

Although several constitutional chromosome conditions are known to have increased susceptibility to various forms of cancer, very little is known regarding the magnitude of risk for malignancy associated with distal 22q11.2 deletion syndrome. In view of this finding we suggest that patients diagnosed with distal 22q11.2 deletion syndrome undergo careful prolonged monitoring for this type of tumour.

This case demonstrates the need to carefully assess regions found to be deleted in individuals, referred for dysmorphia and/or developments delay, by array-CGH for the presence of genes known to be implicated in malignancy.

Introduction

Unlike DiGeorge/Velocardiofacial syndrome (DGS/VCFs) there have been few reports of patients with the distal 22q11.2 deletion syndrome [1], [9], [11], [12], [13], [14]. Distal 22q syndrome is characterised by microdeletions immediately telomeric to the DGS/VCFs, typically encompassing the BCR gene. Several low copy repeats (LCRs) are present at 22q11.2, making this band highly susceptible to microdeletions and microduplications. At least eight LCR clusters have been identified at 22q11.2 and have been named LCR22s [4]. The four centromeric LCRs (LCR22-2, LCR22-3a, LCR22-3b and LCR22-4) have been implicated in DGS/VCFs. The distal 22q syndrome deleted region is typically flanked by LCR22-4 and LCR22-6 [9]. Phenotypic signs of distal 22q syndrome include mild developmental delay, subtle facial dysmorphism and delayed growth.

The distal 22q11.2 deletion encompasses the INI1/SMARCB1 tumour suppressor gene. Biallelic inactivation of this gene is characteristic of atypical teratoid/rhabdoid tumour [2], [15]. Atypical teratoid rhabdoid tumours (AT/RT) are highly malignant childhood tumours. Less than 10% of these tumours are diagnosed in patients whose age is more than 5 years [2]. This tumour may occur as a consequence of constitutional or somatic haploinsuffiency for the INI1/SMARCB1 gene and is frequently associated with intratumoral loss of heterozygosity (LOH) caused by a second hit [16]. Although most tumours result from double hit somatic mutations of INI1/SMARCB1, germline mutations of INI1/SMARCB1 that predispose patients to AT/RT have been well described [2], [6] However, several cases associated with germline deletions of INI1/SMARCB1 have been reported [3], [5], [7], [8], [17]. In this report we discuss the link between this constitutional syndrome and a predisposition to this type of tumour.

Section snippets

Clinical report

Our patient was born to non consanguineous European-New Zealand parents. His birth weight was 3 kg, length 48 cm and head circumference 31.5 cm. He was breast fed with no feeding problems. At 2 weeks-of-age he presented with bilateral inguinal hernias and at 6 weeks with pyloric stenosis. He showed normal motor development but language was delayed. At 3 years he developed a tic and was diagnosed with Tourette syndrome, dyspraxia, obsessive compulsive traits and inattentive type ADHD.

At 18 years he

Methods and results

A standard GTG-banded karyotype was normal at 550 bands. No deletion of 22q11.2 was detected by FISH analyses using the Vysis (Abbott) TUPLE1 probe.

Array comparative genomic hybridisation (aCGH) studies that used the Agilent 4 × 44 K human (build 36) array revealed a 3.4 Mb deletion at 22q11.2 from basepair 19712953 to 23129417 (maximum size). The INI1/SMARCB1 gene that, when mutated or deleted, is known to be associated with rhabdoid tumours and schwannomas was among the 40 to 42 genes known to be

Discussion

Distal 22q11.2 deletion syndrome was first identified by Raunch et al. [11], [12] and found serendipitously by Ravan et al. [13] in eight patients with unexplained developmental delay who were being tested by subtelomeric FISH analysis. They were noted to have loss of the BCR (control) probe compatible with an interstitial deletion at 22q11.2. Subsequently, there have been additional cases reported [1], [9], [14]. Although to date patients have been found during FISH analysis, it is to be

Acknowledgements

We would like to thank the members of the clinical, cytogenetic and molecular genetic teams at Central and Southern Genetic Services for their help and support. We also wish to thank the family of our patient for their kind cooperation.

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