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Editor—Deletions of the terminal region of the long arm of chromosome 11 (bands 11q23.3-11q24) are associated with a clinically recognisable phenotype, also called Jacobsen syndrome (JS).1 Reports on more proximal 11q deletions are rare. This is the second report describing a de novo interstitial deletion of the 11q22.3-q23.2 region. The first described a de novo interstitial deletion of the 11q22.3-q23.2 region in a mildly retarded male with minor dysmorphic signs (high and narrow palate, low set, dysplastic ears, small hands and feet, and slender fingers) and epileptic seizures.2 However, no FISH studies were performed in this patient.
In this report we describe a small de novo interstitial deletion in the long arm of chromosome 11 (bands q22.3-q23.2) in a 2 year 8 month old boy with mild developmental delay and without major associated dysmorphic features or a clinically recognisable phenotype.
The proband, a boy, is the second and youngest child of healthy, non-consanguineous parents. His 5 year old sister is normal. Pregnancy and delivery, at 39 weeks, were normal. Birth weight was 3130 g, length 49 cm, and head circumference 33.5 cm. Clinical examination in the neonatal period was normal, apart from mild axial hypotonia. Motor development was slightly retarded and he walked without support at the age of 17 months.
Now, at the age of 2 years 8 months, psychomotor development is borderline normal (2 years 2 months to 2 years 4 months on the Bayley Developmental scale). Social contact is adequate but expressive language is mildly retarded at a developmental level of 2 years. Height is 89.5 cm (10th centile), weight 12.5 kg (10th centile), and head circumference 48 cm (3rd centile for age). Except for the relative microcephaly and mild trigonocephaly, craniofacial dysmorphism is mild and non-specific, including a somewhat large mouth with a thin upper lip and everted lower lip and rather large and everted ears. Both thumbs are proximally implanted. Further clinical and neurological examinations were normal. Additional examinations including MRI scan of the brain, metabolic screening, and ophthalmological examination were normal.
Cytogenetic studies were performed using PHA stimulated lymphocytes according to standard cytogenetic procedures. G banded chromosome analysis showed an interstitial deletion of the long arm of chromosome 11 (q22.2-q23.1) (fig 1). The karyotype was 46,XY,del(11)(pter→q22.3::q23.1→qter). The parental karyotypes were normal.
FISH with chromosome 11 specific paint probe (Cambio) showed no translocation of chromosome 11 material (fig 2A). FISH analysis was performed with five YAC probes (878C12, 876G04, 801E11, 755B11, and 742F09), BAC442e11, and three cosmid probes that map to the 11q22-11q23 region. BAC442e11(RPC11 human BAC library, Roswell Park Cancer Institute) has been recently reported and spans the t(11;22) breakpoint on chromosome 11.3 Cosmid probes 4746 and 4748 cover theMLL gene region and 2072c1 is a subtelomeric probe (table 1).4
FISH results defined the extent of the deletion (from q22.3 and q23.2). The proximal boundary of the deleted region is between D11S1762/D11S1339 and D11S1167 because FISH with YAC878C12 gave a signal on the deleted chromosome, whereas the terminal boundary is placed proximal to the MLL locus (fig 2B, C, D, E, F). Chromosomes were viewed with a Zeiss Axioplan epifluorescence microscope. For digital image analysis the Cytovision System (Applied Imaging) was used.
Chromosomal region 11q22-q23 is apparently prone to instability (recombination, breakage, or rearrangement). The breakpoints of the classical constitutional t(11;22) and the breakpoints in the majority of cases with terminal 11q deletions and derivative chromosomes 11 are located in this region. This region is often involved in multiple tumour associated rearrangements of chromosome 11 and distally lies theMLL gene region that is frequently rearranged in haematopoietic malignant disorders.5 On the telomeric side of MLL is the fragile site FRA11B and also the Jacobsen syndrome breakpoints (11q23.3-11q24.2).1 3 Consequently the region could be considered as a hot spot of chromosomal recombination and breakage.
In this case, the deletion is smaller than the previously reported deletions on 11q, for example, deletions critical for the diagnosis of Jacobsen syndrome (MIM 147791)1 or larger deletions involving the 11q22-q23→11qter region.6-9
The fragile site at 11q23.3 (FRA11B) is linked to some Jacobsen syndrome breakpoints (10% of the cases) but the majority are located distal to FRA11B. It was proposed that JS is not a single disease but a collection of different genetic disorders with overlapping phenotypes. The phenotypic variability observed is because of the variation of breakpoints and the different genes involved.1 10 11Thus, the 11q22.3-q32.2 deletions in the present patient could be considered as a part of the spectrum of 11q deletions resulting from a similar mechanism, with the more distal deletions resulting in Jacobsen syndrome and the more proximal resulting in a milder phenotype.
In the present case, Bac442e11, which spans the t(11;22) breakpoint in 11q23, was deleted. This BAC clone is related to a palindromic AT rich region.12 The mechanism of formation of the deletion in the reported case could be consistent with the one proposed by Akgun et al.13 They proposed that in mammals palindromic DNA sequences can lead to the formation of unstable DNA structures, such as single stranded hairpin and double stranded cruciform structures, and they hypothesised that a small disruption of symmetry in the palindrome could stabilise the locus. To explain their results, they proposed two different models that could explain the formation of deletions and translocations. According to one model, replication slippage could result in two sided palindrome deletions spanning the tip of the hairpin and create a product with a deletion in the palindrome. This mechanism could explain the deletion in the present patient. According to the second model, a single strand nick in the tip of the hairpin could result in a double strand break and then lead to illegitimate recombination. The second model could be consistent with the formation of the t(11;22).13