Distal deletion, del(2)(q33.3q33.3), in a patient with severe growth deficiency and minor anomalies

INTRODUCTION

Small interstitial deletions within the distal segment of 2q including band 2q33 are rare and, so far, did not go along with a defined phenotype. While wrinkly skin as the most striking feature was described in three members of one family with deletion of 2q32–q33 [Kreuz and Wittwer, 1993], a Seckel-like syndrome was described in a proband with deletion of 2q33–q34 [Courtens et al., 1997], and the Pierre-Robin sequence associated with further anomalies was ascertained in a patient with deletion of 2q33.1–q33.3 [Vogels et al., 1997]. The patterns of anomalies of the other patients were different and relatively non-specific.

We report a further patient with deletion of band 2q33.3 with relatively non-specific pattern of growth retardation, developmental delay and minor physical anomalies. Clear definition of the deleted segment was only possible through the application of fluorescent in situ hybridization (FISH) with band-specific molecular probes.

CLINICAL REPORT

The propositus, an 18-month-old boy, was the product of the first pregnancy of a 27-year-old healthy mother and her 28-year-old partner. The pedigree is unremarkable; consanguinity is unlikely. Due to primary infertility, the conception was achieved by in vitro fertilization. Perinatal history was non-contributory. The boy was born at 39 weeks of gestation with a birth weight of 2,350 grams (below the 5^th centile), birth length of 48 cm (below the 10^th centile), and a head circumference of 30 cm (below the 3^rd centile). The following clinical findings were noticed at birth: relatively small face compared to the skull size, trigonocephaly with bifrontal narrowing, prominent occiput, telecanthus, inner epicanthic folds, downslanting palpebral fissures, posteriorly rotated, prominent, low-set ears, microstoma, umbilical hernia, bilateral fifth finger camptodactyly, and broad and short finger nails. Hair was sparse for the first months after birth and is now thin.

In complementary investigations, ophthalmologic examination revealed normal findings. Abdominal ultrasonography, cranial magnetic resonance, and cardiac echography detected no organ anomalies.

His major problem was severe growth retardation (at the age of 18 months, weight was 5,750 g, length was 71 cm, and head circumference was 43 cm - all values far below the third centile). The first tooth appeared at 12 months of age. Muscular hypotonia was treated with physiotherapy. His development at 18 months of age corresponded to seven months in gross motor skills. He was still unable to sit up, but he can now keep a sitting position and with some support can keep a standing position. He has no speech; he still babbles (Fig. 1a,b).

METHODS

RESULTS

GTG-banded chromosome preparations at a 400–600 band level were suggestive of a small interstitial or terminal deletion in 2q. Chromosome analysis of both parents revealed normal results, with no indication of a rearrangement in 2q. FISH analysis of karyotypes from the patient with a chromosome-2-specific painting probe showed both chromosomes 2 fully painted and no signals on other chromosomes, thus excluding involvement of another chromosome in a rearrangement. Metaphase FISH examination with a subtelomeric probe mapping to 2q disclosed signals on both the normal and the abnormal homologue indicating integrity of the subtelomeric region. Thus, an interstitial deletion was assumed. Several region-specific YACs were used to map the deleted segment: FISH with y828-e-8 (D2S116, 205 cM, mapping to 2q33.3) and y941-f-2 (D2S369, 209 cM, mapping to 2q33.3–q34.1) showed a signal only on the normal homologue, thus indicating deletion of band 2q33.3 (Fig. 2). y860-h-8 (D2S128, 217 cM, mapping to 2q34), the overlapping marker y961-c-6 (D2S128, 217 cM, mapping to 2q34–q35), and y755-b-5 (D2S161, 197cM, mapping to 2q32) showed signals on both homologues.

Thus, the examinations indicated a small interstitial deletion involving segment 2q33.3, with a minimal deletion of 4.8 mB, and the karyotype can be written as 46,XY,del(2)(q33.3q33.3) or 46,XY,del(2)(q33.3q34.1) de novo.

DISCUSSION

A small distal interstitial deletion within 2q was suspected on GTG-banded karyotypes in our patient, but it could not be confidently determined using only banding techniques. His phenotype, showing severe growth retardation, a mild dysmorphic pattern, and moderate to severe growth retardation, is suggestive of a minor structural chromosome aberration. It was only through the application of fluorescent in situ hybridization with band-specific probes that the deletion could be demonstrated and exactly localized (at 2q33.3).

Table I presents cytogenetic and clinical data from patients from the literature with deletions within 2q which overlap with the 2q33 deletion in the patient of the present report. In all but the case of Courtens et al. [1997], no FISH or molecular methods were applied with the purpose of confirming the aberration suspected from banded karyotypes and of defining the breakpoints on a molecular level. Thus, there is the possibility that some of these aberrations were incorrectly defined. In fact, re-investigation of cases in which breakpoints were initially cytogenetically defined often results in a different definition [Schinzel, 2001, in press]. As seen in Table I, the clinical patterns, especially the minor anomalies, differ considerably between the different patients. This is even true for the only case in which the deletion breakpoints were most similar to those in our patient [Vogels et al., 1997]. These two patients did not share dysmorphic features apart from such non-specific ones as small mouth and abnormal ears.

The fact that only two patients with 2q33 deletions have so far been reported in the literature does not allow the conclusion that this deletion occurs extremely rarely; it is more likely that it is often overlooked and rarely reported because of the relatively non-specific and non-spectacular pattern of abnormalities in these patients. Further reports on patients with well determined similar deletions are necessary before a clinical phenotype related to deletion of band 2q33 or even 2q33.3 can be established. Our patient, however, again shows the importance of molecular cytogenetic methods for the confident determination of breakpoints in small autosomal deletions.