Interstitial deletion 2p11.2–p12: Further delineation

The recent publication of a patient with an interstitial deletion of 2p11.2–p12 and the review of earlier published patients [Tzschach et al., 2009] urged us to report on yet another case we have recently been able to study. The patient is the third child of healthy, non-consanguineous parents. Family history is unremarkable. The patient was born at term, after an uneventful pregnancy and normal vaginal delivery. Birth weight was 3,300 g (25–50th centile) and length at birth was 51 cm (50–75th centile); head circumference was not recorded. The infant did well in the immediate neonatal period. A small muscular ventricular septum defect closed spontaneously. Because of recurrent urinary tract infections urologic examination was performed which showed bilateral vesicoureteral Grade III reflux and which was surgically corrected. He has followed a delayed motor development (sitting at 13 months, walking at 24 months), and especially speech was delayed (first babbling sounds at 3.5 years). At 5.9 years his height was 106 cm (5th centile), weight was 19 kg (25–50th centile), and head circumference was 51.0 cm (25–50th centile). Facial features included a prominent occiput, high forehead, extra whorl in the anterior hair line, long face, horizontal palpebral fissures, broad high nasal bridge, broad ridge and tip, thin upper vermillion, and large, protruding ears (Fig. 1). His genitalia were normal with normal sized descended testes. He had bilateral fifth finger clinodactyly but limbs were otherwise normally formed. He made good eye contact, was hyperactive, had a happy predisposition, and made only babbling sounds. In the lower extremities the reflexes were increased, and slight hypertonia was detected. His gait was wide based with hip circumduction and feet turned outward (Fig. 2). In addition, arms were uplifted with flexed elbows and downward turned hands. Ophthalmological and audiological investigations, EEG and brain MRI did not show anomalies. Chromosomal analysis of peripheral lymphocytes showed a de novo interstitial deletion of the short arm of chromosome 2: 46,XY,del(2)(p11.2p12). Microarray comparative genomic hybridization (CGH-microarray) with the Human Genome CGH 105A Oligo Microarray kit (Agilent technologies, Inc., Palo Alto, CA) showed that the deletion was approximately 10.43 Mb in size spanning the bases 76,854,464–87,287,935 on chromosome 2 (genomic positions according to UCSC genome browser May 2004 assembly). In three patients including a pair of sibs molecular characterization of breakpoints of the 2p11.2–12 deletion has been reported [Barber et al., 2005; Tzschach et al., 2009]. The deleted segments were 11.4 Mb [Tzschach et al., 2009], 10.4 Mb (present case) and 7.5 Mb [Barber et al., 2005] in size. The largest deletion extended about 4 Mb more proximally into the gene rich 2p11.2 band than the other two (Fig. 3). Only the patient with the largest deletion had microcephaly [Tzschach et al., 2009]. The minimal region for microcephaly is the region between 87.2 and 91.5 Mb, located in band 2p11.2. Sixteen RefSeq genes are located in this region (UCSC Genome Browser, release March 2006, http://genome.ucsc.edu/ cgi-bin/hgGateway). From at least 8 of them (PLGLB1, PLGLB2, KRCC1, THNSL2, FOXI3, C2orf51, EIF2AK3, and LOC654342) expression in human fetal or adult brain has been shown (http:// biogps.gnf.org). No gene is known to have a function that may lead to microcephaly, and none of the known animal models has been reported to show microcephaly. This makes identification of any likely candidate gene(s) difficult at the present stage. All patients had somewhat similar facial features, especially a dolichocephaly, prominent forehead and broad nasal bridge which sometimes extended to broadness of the nasal ridge and tip. All had a developmental delay, with marked expressive language problems in some [Barber et al., 2005]. In all patients the deleted segment included REEP1, which can cause autosomal dominant spastic paraplegia type 31 when mutated [Z€ uchner et al., 2006]. Only the present patient showed lower extremities hypertonia and a spastic,