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Autosomal deletions or chromosomal haploinsufficiency syndromes are observed in 1 in 7000 live born infants1 and may cause multiple malformations, growth failure, and mental retardation. Deletions on the short arm of chromosome 3 have been reported in 35 cases and have been divided into two groups: deletion 3p syndrome2 with breakpoints between 3p24 and 3p25 and proximal deletion 3p syndrome3 with different breakpoints between 3p11 and 3p21.2. The first reported case of an interstitial deletion of chromosome 3p22.2-p24.2 in a 6 year old male with developmental delay is presented here.
The proband was the fourth child born, in England, to healthy, unrelated, white parents. There was no family history of note. He was born vaginally following spontaneous onset of labour at 41 weeks of gestation after an uneventful pregnancy and weighed 3140 g (10th centile). A murmur was noted shortly after delivery and echocardiography confirmed the presence of a small, perimembranous ventricular septal defect. His early milestones were reported as normal, but he was referred for assessment of developmental delay when aged 16 months. He made good progress following input from a child development unit. He walked at 23 months and had speech delay. He was reassessed three months after arrival in New Zealand at the age of 3.5 years. He had global developmental delay and it was felt he had some hearing impairment. His language skills were poor, only speaking occasional two to three word sentences by the age of 4 years, although his comprehension was felt to be good. He was a sociable child with no behavioural difficulties. He needed nappies at night and help with toiletting in the daytime. He had no other health problems.
On examination at the age of 5.5 years, his height was 100.5 cm (4 cm <3rd centile), weight 16.2 kg (3rd-10th centile), and head circumference 52.7 cm (75th centile). He had mild bilateral fifth finger clinodactyly. He had midface hypoplasia and a prominent forehead, shown in figs 1 and 2. He had posterior angulation of his ears and a thin upper lip. His nipples were widely spaced. His big toes were short and relatively broad and his fourth toe curled under the third toe (fig 3). The fifth toenail was hypoplastic and there was a wide gap and deep groove between the first and second toes. There were no other dysmorphic features and the remainder of the examination was unremarkable.
Audiological assessment showed a right unilateral sensorineural hearing loss (40-45 dB loss). X ray of his foot was carried out because of the unusual appearance of the toes. No significant bony abnormality was seen.
CYTOGENETIC AND FISH STUDIES
Cytogenetic G banded studies on the peripheral blood lymphocytes showed a de novo interstitial deletion of bands p24.2 to p22.2 in the proximal short arm of chromosome 3 (banding level of 550). The resulting karyotype was a de novo 46,XY,del(3)(p22.2p24.2) (fig 4). This finding was confirmed on examination of 60 cells.
Fluorescence in situ hybridisation (FISH) studies were used to confirm the cytogenetic deletion. A whole chromosome 3 painting probe (Oncor, Inc) showed continuous hybridisation along both the short and long arms of both homologues of chromosome 3. Locus specific YAC clones (966g05 locus D3S3714/D3S3680, 938g11 locus D3S1266, 937h04 locus D3S3564, 792d07 locus D3S3678, 802g01 locus D3S658, Max Planck Institute for Molecular Genetics) overlapping the cytogenetic breakpoints showed loss of signal for the locus D3S1266 and D3S3564. The final karyotype has been interpreted as: de novo 46,XY,del(3)(p2.2p24). ish(wcp3, D3S3714/D3S3680x2, D3S1266−, D3S3564−, D3S3678x2, D3S658x2).
Terminal 3p deletions have been described in 24 cases and interstitial proximal 3p deletions3 5-14 in 11 cases and are felt to show distinct phenotypes. In the terminal 3p deletion syndrome, the patients have pre- and postnatal growth retardation, mental retardation, and developmental delay. A number of craniofacial anomalies are also described, including flat occiput, triangular face, hypertelorism, epicanthic folds, synophrys, ptosis, broad and flat nose, and downturned corners of the mouth. The patients also have small hands and supernumerary digits. In the proximal 3p deletion syndrome, the patients have a characteristic facial appearance with narrow forehead, epicanthic folds, short palpebral fissures, broad nasal bridge, and low set, poorly formed ears. Developmental delay is also described. Joint abnormalities may be present including decreased joint mobility, ulnar deviation of the hands, camptodactyly, and calcaneovalgus deformity of the feet.
There have been no deletions published spanning the region 3p22.2-p24.2. In the case reported here, the proband had a number of mild dysmorphic features, global developmental delay, and short stature. These features are frequently described in patients with chromosome deletions and they are likely to be related to the monosomy of the region p22.2-p24.2. This is apparently the first case report with this deletion, which is surprising as, although the features are relatively mild, the combination of growth failure and developmental delay usually leads to a paediatrician checking the karyotype, as these are features associated with chromosomal abnormalities. In this case, it may be that the early response of the patient to effective intervention by the child development team delayed any further testing. The deletion may usually be associated with a milder phenotype and so chromosome analysis is not undertaken. There are other possible explanations for the mild phenotype. A cryptic rearrangement and low level mosaicism were excluded using locus specific probes and an extended examination of 60 metaphases. However, it is not possible to rule out epigenetic modification of the phenotype because of duplication elsewhere in the genome or that the phenotype is mild because the deletion is in a “protected” genomic region.
A meaningful correlation between this deletion and the clinical phenotype is not possible until further cases are described. It may then be possible to contribute further to the knowledge of the morbid anatomy of the human genome.
We acknowledge the German Human Genome project grant No 4673 to HHR for kindly providing the YAC probes.