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Pure trisomy 20p resulting from isochromosome formation and whole arm translocation
  1. R U SIDWELL*,
  2. M-P PINSON,
  4. S-A BYATT,
  7. D M FLYNN*
  1. *Department of Paediatrics, Royal Free Hospital, London, UK
  2. Department of Clinical Cytogenetics, Royal Free Hospital, London, UK
  3. Department of Clinical Cytogenetics, University College London, London, UK
  1. Dr Sidwell, c/o Dr D M Flynn, Department of Paediatrics, Royal Free Hospital, Pond Street, London NW3 2QG, UK.

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Editor—Approximately 33 cases of trisomy 20p have been reported.1-10 Most cases are the product of reciprocal translocations with a few cases arising from inversions. A trisomy 20p syndrome has been difficult to delineate as many cases involve only partial trisomy, often in the presence of partial monosomy of the partner chromosome. We describe a case of pure trisomy 20p arising from de novo isochromosome formation associated with non-reciprocal translocation. This type of chromosome rearrangement is very rare and to date has been described only for isochromosome formation of chromosomes 4p, 5p, 7p, 9p, 10p, and 12p.11 12 13 The rarity of these cases is the result of selection bias as only those partial trisomies compatible with life will be ascertained.

Our case, involving duplication 20p with no other chromosomal imbalance, is important to help delineate this syndrome, which is not yet clearly defined. The boy, now aged 19, had dysmorphic features, mild to moderate learning difficulties, osteopenia, and renal abnormalities. He was the second of two children of unrelated, normal Indian parents aged 35 years (mother) and 37 years (father).

His facial features included epicanthic folds and anteverted, flared nostrils as a baby. As a child and adult he had a low anterior hairline, coarse hair, and laterally arched eyebrows. He had a very prominent, large nose, noticeable as a young child, with a convex nasal bridge and anteverted nostrils, present to a much lesser degree in his father. He had short, upward slanting palpebral fissures, a featureless philtrum, thin vermilion border of the upper lip, and a prominent lower lip. His ears were large and low set with a bilaterally prominent antihelix. He had a high arched palate, moderate micrognathia, and dolichocephalic skull (figs 1 and 2).

Figure 1

(A, B) Front and lateral view of the proband aged 13 months.

Figure 2

(A, B) Front and lateral view of the proband aged 13 years.

He grew normally along the 10th centile, had a pubertal growth spurt at 12 years, and achieved a final height of 170 cm (25th centile), as expected from parental heights, and head circumference of 55 cm (normal).

Developmental delay was apparent with mild hypotonia as an infant, a delay in motor activity with walking achieved at 3 years, and poor coordination. Speech was particularly delayed and there were difficulties with articulation; his first words appearing at 2½ years with slow progression. He received both speech therapy and physiotherapy as an infant and attended a special school for moderate learning difficulties where his achievements were average. He was unable to take any formal examinations, though continued his education after completing his schooling.

He had a congenitally small right kidney, with reflux to the level of the renal pelvis. He had two urinary infections and required prophylactic antibiotics for two years. Serial radioisotope DMSA (2,3-dimercaptosuccinic acid) renal scans showed that the right kidney contributed 8% of the total renal function. He was normotensive and had normal renal function tests. He also had a glandular hypospadias, slight chordee, and an undescended right testis (orchidopexy at 7 years). He also had an umbilical hernia as an infant, glue ears treated with grommets, and astigmatism of both eyes. He had no congenital heart defect.

At 13 months of age, radiographs showed marked generalised osteopenia with collapse of several vertebrae, particularly the 7th and 9th thoracic, platyspondyly, biconcave vertebral bodies, and coarsening of the trabecular pattern (fig 3). He had bilateral coxa valga with subluxation of both hips on x ray as an infant. He sustained a Colles (distal radial) fracture when 9 years old. Bone densitometry scans confirmed the osteopenia and showed improvement (though not achieving normal levels) during puberty. Serial measurements of calcium, phosphate, and alkaline phosphatase, parathyroid hormone, and 25-hydroxycholecalciferol were unremarkable. Cortisol, testosterone, 24 hour urinary calcium, and urinary amino acid measurements were all normal.

Figure 3

Lateral x ray of the spine at 13 months of age.

G banded metaphase chromosomes were karyotyped after routine PHA stimulated peripheral blood culture. Chromosome analysis showed a male karyotype with an isochromosome for the short arm of chromosome 20 and translocation of the chromosome 20 long arm to the short arm of one chromosome 4 (fig 4A).

Figure 4

Der(4)t(4;20)(pter;q11.1),i(20)(q11.1) shown by (A) G banding. (B) Whole chromosome paints for chromosomes 4 (Cy3) and 20 (FITC). (C) Subtelomeric probes for 20p (FITC) and 20q (Cy3) showing 20q signal on der(4)t(4;20). (D) Subtelomeric probes for 4p (FITC) and 4q (Cy3), showing interstitial 4p signal near the breakpoint junction on der(4)t(4;20). (E) All human telomeres probe (FITC) showing interstitial signal on der(4)t(4;20). (F) Probe for D20Z1 (rhodamine) showing similar signals on the normal and isochromosome 20, but lack of signal at the breakpoint junction on der(4)t(4;20). Chromosome 4 was identified by the centromeric signal of D4Z1 (rhodamine). (G) All human centromeres probe (FITC) showing signal at the breakpoint junction of der(4)t(4;20). Chromosome 4 was identified by previous hybridisation with D4Z1 (rhodamine), resulting in a yellow signal.

Examination of 100 cells showed no evidence of telocentric 20p, 20q, or other mosaicism. Both parents of the patient had a normal (46,XX and 46,XY) karyotype.

Further characterisation of the chromosome rearrangement was obtained from fluorescence in situ hybridisation (FISH) studies, in all cases performed following the manufacturer's instructions. Application of whole chromosome paints (WCP) (Cambio) for chromosomes 4 and 20 showed hybridisation of WCP 20 to the isochromosome and to the distal p arm of the der(4)t(4;20) confirming that the translocated material was derived from chromosome 20 (fig 4B).

FISH with probes (Cytocell) mapping to the subtelomere regions of 20p and 20q (fig 4C) showed 20q subtelomeric sequences on the der(4)t(4;20), confirming that the translocated material was derived from the chromosome 20 long arm, and 20p signals were seen at both ends of the isochromosome, confirming it to be an isochromosome for the 20 short arm.

FISH with probes (Cytocell) mapping to the subtelomere regions of 4p and 4q (fig 4D) showed the signal near the breakpoint junction suggesting the possibility of a telomeric breakpoint in 4p. FISH with a probe specific to the Wolf-Hirschhorn region, mapping to D4S96 (Oncor), showed signal on both the normal and abnormal copies of chromosome 4, indicating that there was no deletion of the Wolf-Hirschhorn critical region.

The all human telomeres probe (Oncor) showed an interstitial signal in addition to the expected terminal signals on the der(4)t(4;20), confirming the presence of interstitial telomeric TTAGGG repeat sequence at the t(4;20) breakpoint junction (fig 4E). The presence of interstitial telomeric sequence confirmed that the rearrangement involved either breakage of the 4p telomere or fusion between the 4p telomere and sequence from chromosome 20.

C banding suggested a monocentric isochromosome although C band positive material was present in both arms of the isochromosome and was therefore larger than in the normal 20. No C band positive material was seen on the der(4) at the t(4;20) breakpoint junction.

Application of a chromosome 20 alpha satellite probe (D20Z1, Oncor), showed similar signals on the normal chromosome 20 and the isochromosome 20p, again suggesting a monocentric isochromosome. The der(4)t(4;20), identified by hybridisation with a chromosome 4 alpha satellite probe (D4Z1 Oncor), showed no signal with D20Z1 at the breakpoint junction (fig 4F).

The all human centromeres probe labelled with FITC (Oncor) gave a very small but unambiguous signal at the der(4)t(4;20) breakpoint junction in a proportion of cells (fig 4G). Signal was seen on both chromatids in nine of the 27 cells, on one chromatid in seven cells, and six cells were negative. This variation in signal is almost certainly because of its small size and is not considered to be suggestive of mosaicism. Der(4)t(4;20) was identified by sequential hybridisation with the rhodamine labelled chromosome 4 alpha satellite probe resulting in a yellow signal.

The karyotype was interpreted as 46,XY,der(4) t(4;20)(pter;q11.1),i(20)(q11.1). The translocation is non-reciprocal and the patient therefore appears to be trisomic for 20p without any concomitant loss of material from 4p.

We have described a patient with pure trisomy 20p as a result of a rare type of de novo non-reciprocal chromosome rearrangement involving formation of an isochromosome by a whole p arm and translocation of the residual q arm to another chromosome. Rearrangements of this type are thought to arise from centromere fission, or pericentric breakage followed by isochromosome formation by the p arm and translocation (or fusion) of the acentric or telocentric q arm to the telomere of another chromosome.14 They are thought to be mediated by the presence of intrachromosomal telomere-like repeats which have been detected at many sites including the centromeres of chromosomes 1-6, 8-11, 16, 17, and 20.15 The presence of both alphoid sequences and interstitial telomere sequence has been shown in three cases of telomere-centromere fusion. In two cases the translocation involved an acrocentric chromosome and loss of the acrocentric short arm.16 The third case involved translocation of 12q to 8p with i(12p) formation.13

We were able to show both centromeric repeat sequence and interstitial telomeric sequence at the t(4;20) breakpoint junction. Our results support the interpretation of a break in the pericentric long arm of chromosome 20 close to the end of the alphoid sequences, leading to formation of an isochromosome with fused centromeres and therefore a monocentric appearance. The absence of mosaicism involving normal cells or telocentric 20p or 20q supports a single step aetiology.

As our patient is an example of pure trisomy 20p, the features are of particular importance in helping to delineate the syndrome. Although there are many similarities with previously described patients with trisomy 20p, the most striking differences in our patient are the very prominent nose and the osteopenia (table 1). Van Langenet al 17 produced a table of the clinical picture seen in trisomy 20p; however, 15 cases were included twice in their table (Centerwall and Francke,1 13 cases; Delicado et al,18 one case; Schinzel,19 one case), thus producing inaccurate figures.

Table 1

Clinical features of 32 cases of trisomy 20p1-150

Moderate mental retardation and poor coordination are fairly consistent findings, as is a marked speech delay (with mutism reported in two cases by Taylor et al 20), all of which were present in our case. The dysmorphic features of our case have similarities with some previously reported cases. The distinctive nose is an unusual feature, as many other cases had a short, upturned nose (10 reported in younger children and seven in older children or adults). However, the nose in our patient has a similar appearance to the cases described by Grammatico et al 4 (case 1) and Balesstrazziet al.21

The thick, high arched eyebrows seen in our case were also noted by Grammatico et al. 4 Thick eyebrows were noted by Rudd et al 22 and thin, high arched eyebrows by Funderburket al.23 Epicanthic folds and upward slanting palpebral fissures are frequently seen. Short palpebral fissures have been occasionally described.9 19 24

Renal anomalies have been seen before, but a congenitally hypoplastic kidney, as in our case, has not been seen. Previously reported renal anomalies include duplicated urinary tract and hydronephrosis,20 bilateral polycystic kidneys,8 25 ectopic kidney,24 and duplication of the left renal collecting system.2Hypospadias, as seen here, has been reported in two previous cases.20 26 Cryptorchidism was previously reported by Schinzel et al. 19 A case involving macro-orchidism has been described,21 and one involving a ventrally positioned clitoris and anus.22

Our patient had striking osteopenia first noted at a very young age (13 months). Two previous reports exist of a generalised osteoporosis.2 19 Coxa valga deformity of the hips as seen in our case has been previously reported.19 20 25Skeletal anomalies in trisomy 20p appear to be a variable phenomenon, with vertebral abnormalities the most commonly reported, including fusion of vertebrae, reduction of intervertebral spaces, spina bifida, scoliosis, and kyphosis.

Our case is unusual in being the first reported case of a centromere-telomere fusion resulting in trisomy 20p.