Short reportDiagnosis of distal 22q11.2 deletion syndrome in a patient with a teratoid/rhabdoid tumour
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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Cited by (16)
Malignant rhabdoid tumor of the bladder and ganglioglioma in a 14 year-old male with a germline 22q11.2 deletion
2014, Cancer GeneticsCitation Excerpt :Approximately one third of patients with rhabdoid tumors have a germline mutation or copy number alteration of SMARCB1, and a majority of these are de novo (9). Deletions in this region of chromosome 22 are classified as distal or atypical 22q11.2 deletions, because they are downstream of the commonly deleted region in 22q11.2 that causes DiGeorge or Velo-cardio-facial syndrome (14,16–18). Recently, a distal 22q11.2 deletion syndrome has been described that is phenotypically diverse but includes autism spectrum disorders and subtle facial dysmorphism, including arched eyebrows, low-set ears, a thin upper lip, and a pointed chin as seen in this patient (16–18).
Heart defects and other features of the 22q11 distal deletion syndrome
2013, European Journal of Medical GeneticsCitation Excerpt :Müllerian dysplasia has been observed in two patients with non-overlapping deletions from LCR22-4 to LCR22-5, and LCR22-5 to LCR22-6, respectively [24,31]. Choanal atresia was seen in two patients [16,23], pyloric stenosis was seen in two patients [[32], our patient 3], and hip dysplasia was seen in two patients [3,27]. For all rare phenotypes, it is possible that the cause is polygenic with one of the genes involved being located in the 22q11 distal region.
Rhabdoid tumors
2021, The Hereditary Basis of Childhood Cancer