Expanding the phenotype of duplication of the Rubinstein–Taybi region on 16p13.3

Several cryptic chromosome imbalances detected by array-CGH analysis have outlined new genotype–phenotype correlations and isolated a number of distinctive clinical conditions. Duplication of the subtelomeric region of chromosome 16p13 (dup16p13) is emerging as one of the most common contiguous gene disorders, and it is associated with a recognizable phenotype of psychomotor and growth retardation, microcephaly, seizures, distinctive facial appearance, cardiac, and hands anomalies [Kokalj-Vokac et al., 2000; De Ravel et al., 2005; Ruiter et al., 2007]. The subtelomeric part of the short arm of chromosome 16 is a gene-rich region encompassing more than 250 genes, including CBP, whose mutation and microdeletions cause Rubinstein–Taybi syndrome [Hennekam, 2006]. The individual contribution of each of these genes to the dup16p13 phenotype is unknown at present, although a possible appraisal to this problem can be attained by genotype–phenotype correlation analysis of patients heterozygous for duplications affecting individual sub-bands. Recently, Marangi et al. [2008] have reported on a boy with duplication of the 16p13.3 region, and depicted the characteristic phenotype associated with this rare imbalance, which have considered most likely related to the overexpression of a single-gene. At present the clinical description of this new disorder is available only for three patients. We report on an additional case, which corroborates and expands this phenotype. The patient, a 10-year-old was the first child of healthy parents with a noncontributory family history. A second daughter was normal. Pregnancy at term was unremarkable. Birth weight was 2,650 g (5th centile), length 49 cm (25th centile), OFC 34 cm (25th centile). Apgar was 6, 6, and 8 at 1, 5, and 10 min, respectively. Feeding difficulties were reported in the first year of life. Developmental milestones were retarded. She was sitting unsupported at 10 months and walked independently at 24 months. Her first words were spoken at 3 years. Mental retardation was considered moderate with inadequate social interaction and no behavioral problems. Results of EEG and brain MRI were normal. When evaluated by us at 10 years, height was 158 cm and OFC 56 cm (both >97th centile). She had a characteristic long face with round chin, asymmetric upslanted palpebral fissures, unilateral ptosis at right, broad eyebrows, rounded nasal tip, thick alae nasi, and anteverted nostrils. The philtrum was rather long with high pillars and full lips. Ears were low set, non-prominent nor grossly dysmorphic (Fig. 1a). There was a mild pectus excavatum and an obvious limitation in the forearm pronosupination and elbows’ extension. Fingers 1–4 were rather long and tapering at their extremities, with short 5th fingers. Interphalangeal movements were also limited and the distal interphalangeal creases were absent or replaced on some fingers by additional horizontal creases crossing the middle phalanges (Fig. 1b). Feet were characterized by bilateral cutaneous syndactyly of toes 2–3, with camptodactylous toes three and four (Fig. 1c). Array-CGH analysis was performed using a genomic oligonucleotide-based array with an average spacing of 75 Kb all over the genome (44B Chip; Agilent Technlogies, Walldbronn, Germany). This study disclosed a 16p13.3 duplication from A_14_P139336 (2,707,954 bp) to A_14_P128864 (5,222,246 bp) probes, which were the first and the last duplicated oligonucleotide from the telomere, respectively (Fig. 2a). The duplicated segment spanned for about 2.5 Mb and encompassed 68 RefSeq genes, based on UCSC Genome Browser (http://genome.ucsc.edu/; March 2006