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Whole-exome sequencing of a patient with intellectual disability and without recognisable phenotype yielded a mutation in the intron20 splice donor site of CREBBP. Mutations at different positions within the same intron20 splice donor site were observed in three patients clinically suspected as having Rubinstein-Taybi syndrome (RSTS). All mutations were de novo and likely disease-causing. To investigate a putative difference in splicing between the patient without RSTS phenotype and the three patients with the RSTS phenotype, we analysed the effects of these mutations on splicing of the pre-mRNA of CREBBP. As no RNA of patients was available, we generated a new and improved exon-trap vector, pCDNAGHE, and tested the effect of the various mutations on splicing in vitro. All mutations lead to skipping of exon20. In one of the patients with an RSTS phenotype, there was also some normal splicing detectable. We conclude that the splicing pattern obtained by exon-trapping cannot explain the difference in phenotype between the patient without the RSTS phenotype and the patients with clinical RSTS. Patient or tissue-specific splice effects as well as modifying genes likely will explain the difference in phenotype.

Background: Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomalies-intellectual disability syndrome. One of the complications is keloid formation. Keloids are proliferative fibrous growths resulting from excessive tissue response to skin trauma., Objectives: To describe the clinical characteristics of keloids in individuals with RSTS reported in the literature and in a cohort of personally evaluated individuals with RSTS., Patients and Methods: We performed a literature search for descriptions of RSTS individuals with keloids. All known individuals with RSTS in the Netherlands filled out three dedicated questionnaires. All individuals with (possible) keloids were personally evaluated. A further series of individuals with RSTS from the U.K. was personally evaluated., Results: Reliable data were available for 62 of the 83 Dutch individuals with RSTS and showed 15 individuals with RSTS (24%) to have keloids. The 15 Dutch and 12 U.K. individuals with RSTS with keloids demonstrated that most patients have multiple keloids (n > 1: 82%; n > 5: 30%). Mean age of onset is 11·9 years. The majority of keloids are located on the shoulders and chest. The mean length × width of the largest keloid was 7·1 × 2·8 cm, and the mean thickness was 0·7 cm. All affected individuals complained of itching. Generally, treatment results were disappointing., Conclusions: Keloids occur in 24% of individuals with RSTS, either spontaneously or after a minor trauma, usually starting in early puberty. Management schedules have disappointing results. RSTS is a Mendelian disorder with a known molecular basis, and offers excellent opportunities to study the pathogenesis of keloids in general and to search for possible treatments., (© 2014 British Association of Dermatologists.)

Aims: To delineate the nature and frequency of ocular pathology in Rubinstein-Taybi syndrome (RTs)., Methods: Literature was searched for reports describing ocular symptoms in patients with RTs. 24 RTs patients (out of a total of 73 Dutch known RTs individuals) were selected for ophthalmological and electrophysiological examination, selection being based only on the distance between a patient's residence and the place of investigation., Results: Most frequently reported eye anomalies in the literature were lacrimal duct obstruction, corneal abnormalities, congenital glaucoma, congenital cataract, and colobomata. Abnormalities of almost any eye segment have been published in case reports. Ophthalmological examination of 24 Dutch RTs patients showed a visual acuity

Rubinstein-Taybi syndrome (RTS) is a multiple congenital anomalies and mental retardation syndrome characterized by facial abnormalities, broad thumbs, and broad big toes. We have shown previously that disruption of the human CREB-binding protein (CBP) gene, either by gross chromosomal rearrangements or by point mutations, leads to RTS. Translocations and inversions involving chromosome band 16p13.3 form the minority of CBP mutations, whereas microdeletions occur more frequently (approximately 10%). Breakpoints of six translocations and inversions in RTS patients described thus far were found clustered in a 13-kb intronic region at the 5' end of the CBP gene and could theoretically only result in proteins containing the extreme N-terminal region of CBP. In contrast, in one patient with a translocation t(2;16)(q36.3;p13.3) we show by using fiber FISH and Southern blot analysis that the chromosome 16 breakpoint lies about 100 kb downstream of this breakpoint cluster. In this patient, Western blot analysis of extracts prepared from lymphoblasts showed both a normal and an abnormal shorter protein lacking the C-terminal domain, indicating expression of both the normal and the mutant allele. The results suggest that the loss of C-terminal domains of CBP is sufficient to cause RTS. Furthermore, these data indicate the potential utility of Western blot analysis as an inexpensive and fast approach for screening RTS mutations., (Copyright 2000 Wiley-Liss, Inc.)

Rubinstein-Taybi syndrome (RTS) is a malformation syndrome characterised by facial abnormalities, broad thumbs, broad big toes, and mental retardation. In a subset of RTS patients, microdeletions, translocations, and inversions involving chromosome band 16p13.3 can be detected. We have previously shown that disruption of the human CREB binding protein (CREBBP or CBP) gene, either by these gross chromosomal rearrangements or by point mutations, leads to RTS. CBP is a large nuclear protein involved in transcription regulation, chromatin remodelling, and the integration of several different signal transduction pathways. Here we report diagnostic analysis of CBP in 194 RTS patients, divided into several subsets. In one case the mother is also suspect of having RTS. Analyses of the entire CBP gene by the protein truncation test showed 4/37 truncating mutations. Two point mutations, one 11 bp deletion, and one mutation affecting the splicing of the second exon were detected by subsequent sequencing. Screening the CBP gene for larger deletions, by using different cosmid probes in FISH, showed 14/171 microdeletions. Using five cosmid probes that contain the entire gene, we found 8/89 microdeletions of which 4/8 were 5' or interstitial. This last subset of microdeletions would not have been detected using the commonly used 3' probe RT1, showing the necessity of using all five probes.

Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly syndrome comprising mental and growth retardation, broad thumbs and great toes, and an unusual face. The classical facial appearance is well-established, striking and easy to recognize. It includes downslant of the palpebral fissures, epicanthic folds, ptosis, strabismus, highly arched palate, simple ears and a small mouth. The nose is distinctive with a beaked appearance, broad fleshy bridge, deviated septum and short low columella. Previous studies have documented considerable change in this facial phenotype with time. In this study, we evaluated 31 individuals with RTS from Great Britain and The Netherlands. They range in age from 1 to 39 years. Detailed craniofacial measurements were obtained on each subject and composite pattern profiles were compiled. There was remarkable concordance of patterns at all ages from infancy to adulthood. Microcephaly was present consistently. The head was relatively round with head width equal to head length. There was narrowness at the skull base with relative broadening of the minimal frontal diameter and lower facial width. The mouth was small and ears were broad and short. Eyes were wide-spaced in comparison to upper facial width and head circumference. The child under 4 years demonstrated some differences. Width and depth of the upper face exceeded that of the lower face, whereas with increasing age, mandibular dimensions were closer to normal than their maxillary counterparts. Despite these differences, the similarity of the profiles of all age groups seems to belie the phenotypic changes that can be appreciated subjectively. This suggests that major components of the change in appearance are those which have not been assessed in this study, such as palpebral fissure slant, deviation of the nasal bridge, presence of epicanthal folds or ptosis; or for which norms are not available, for example, beaking of the nose, and low nasal septum.

The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features. Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16p13.3 (refs 4-8). Here we report that all these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-AMP-regulated gene expression. We show that RTS results not only from gross chromosomal rearrangements of chromosome 16p, but also from point mutations in the CBP gene itself. Because the patients are heterozygous for the mutations, we propose that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RTS and possibly the propensity for malignancy.

In the accompanying paper, a chromosomal localization of the Rubinstein-Taybi syndrome by cytogenetic investigations with fluorescence in situ hybridization techniques at chromosome 16p13.3 is described. We investigated 19 of these patients and their parents (a) to ascertain the parental origin of the chromosome with the deletion in families where such a deletion was detected, (b) to disclose whether uniparental disomy plays a role in etiology, and (c) to compare clinical features in patients with a deletion to those in individuals in whom deletions were not detectable. Molecular studies showed a copy of chromosome 16 from each parent in all 19 patients. Uniparental disomy was also excluded for five other chromosome arms known to be imprinted in mice. None of the probes used for determining the origin of the deleted chromosome proved to be informative. The clinical features were essentially the same in patients with and without visible deletion, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces. A small deletion at 16p13.3 may be found in some patients with Rubinstein-Taybi syndrome. Cytogenetically undetectable deletions, point mutations, mosaicism, heterogeneity, or phenocopy by a nongenetic cause are the most probable explanations for the absence of cytogenetic or molecular abnormalities in other patients with Rubinstein-Taybi syndrome.

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective conformation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome.

The Rubinstein-Taybi syndrome is a classical multiple congenital anomaly syndrome. The classical gestalt is striking and poses few diagnostic problems, but sometimes diagnosis is extremely difficult. In this paper the change in facial appearance of affected individuals is demonstrated, to improve insight into the evolution of the phenotype and to increase its diagnostic potential.

Forty individuals with Rubinstein-Taybi syndrome were tested using an extensive test battery to obtain more insight about their intelligence level, social competency, temperament, and behavior as well as articulation and receptive and expressive language level. Examination of individuals in the Netherlands who have this rare syndrome has been extensive, allowing some generalizations to be made. The intelligence level of affected individuals is usually low, although some persons have much higher scores than do others. The tested individuals were remarkably consistent in their social competency, temperament, and behavior. They were able to make good use of their limited verbal abilities. Comparable studies of other groups of persons with a specific syndrome are needed to determine whether the present findings are specific for Rubinstein-Taybi syndrome or may be found among persons with other syndromes.

A roentgencephalometric study to compare the facial morphology of 18 individuals affected with Rubinstein-Taybi syndrome and 25 of their parents was performed. The main findings in the affected individuals were shortening of facial height and depth, cranial base length, a marked decrease in size of the mandible, and a steep cranial base. A change with age was found for some dimensions. The pattern variability indices were high, indicating an abnormal craniofacial profile. The correlations between most patients were high, although this was less expressed for the younger patients. The parents had a normal pattern profile and pattern profile variability indices. The correlation between parents and their affected children was low. This study suggests that pattern profile analysis of cephalometric measurements may be a useful diagnostic tool in Rubinstein-Taybi syndrome. However, comparable studies of large groups of patients, especially of a younger age, are needed for further ascertainment of normal values in individuals with Rubinstein-Taybi syndrome at different stages of facial development.

Oral findings in 45 patients with Rubinstein-Taybi syndrome living in The Netherlands are compared with those from the literature. The main non-dental findings were thin upper lip, small oral opening, pouting lower lip, retro/micrognathia, and apparently higher arched, narrow palate. Cleft uvula, cleft palate, or, rarely, cleft upper lip can be part of the syndrome. Timing of the eruption of deciduous and permanent dentition is normal. Sixty-two percent of patients have malpositioned, crowded teeth. Marked caries was found in 36% and was possibly caused by problems in dental care due to the small opening of the mouth, malposition and malformation of the teeth, and non-cooperation of the patients. Hypodontia, hyperdontia, and natal teeth can be manifestations of the syndrome. In 73% of all patients and in 92% of all permanent dentitions, talon cusps were found. Two or more talon cusps are rarely found in the normal population or other syndromes. Therefore, this finding strongly supports the diagnosis of Rubinstein-Taybi syndrome in patients in whom this diagnosis is suspected.

In order to derive standard curves for height, weight, head circumference (OFC), weight-for-height, and height velocity, we obtained serial measurements in 95 patients with the Rubinstein-Taybi syndrome. Fifty individuals were part of an American study and 45 were ascertained in the Netherlands. Prenatal growth appears to be normal in the Rubinstein-Taybi syndrome, but height, weight, and OFC rapidly fall below the 5th centile in the first few months of life. Height velocity is somewhat below the mean but within the normal range except for the lack of a pubertal growth spurt. This phenomenon probably contributes to the short stature which is seen in these patients. Males are overweight for height during childhood while females are overweight during adolescence. The average OFC in males is smaller than in females. In general only a minority of adult patients are microcephalic.

Metacarpophalangeal pattern profile (MCPP) was determined in 49 radiographs of 40 patients with Rubinstein-Taybi syndrome. Two recognizable hand profiles were seen, depending on the configuration of the thumb and on age. Patients with a straight thumb showed a short first proximal phalanx, and short third medial phalanx. Patients with a radially deviated thumb had a short first proximal phalanx. Depending on age, a relatively large (infancy) or markedly short (older patients) first distal phalanx was found. The similarity between the patients was high. A third group of patients did not show a particular hand profile, but only small hand bones. The pattern variability indices were high in all groups of patients. MCPP analysis in Rubinstein-Taybi syndrome seems to be a powerful, but not pathognomonic, diagnostic tool.

This study reports the physical and radiographic characteristics of 45 patients with Rubinstein-Taybi syndrome living in The Netherlands. All had broad halluces, but only 39 patients had broad thumbs. Microcephaly was present in 35% of patients. In addition to the well-known characteristics, persistent fetal pads, a shawl scrotum, and a high frequency of fractures were found in several patients. Morbidity was mainly determined by the mental handicap, constipation, and recurrent upper respiratory infections, probably due to abnormal anatomy in the craniofacial region. Easy collapsible laryngeal walls may cause problems in sleep and anaesthesia.

Epidemiologic data on 45 patients with Rubinstein-Taybi syndrome from the Netherlands and 50 patients from the USA are compared with data from 407 patients reported in the literature. The 502 probands had a total of 708 sibs, including one probable recurrence. In 12 of 13 proven or possible monozygotic twins both children were affected. Two patients have reproduced with one affected and 2 normal offspring. The empiric recurrence risk figure for sibs is 0.1%. The recurrence risk for offspring of affected individuals could be as high as 50%. The cause of the syndrome remains unknown. There were no clues for autosomal recessive or X-linked inheritance, nor for a teratogenic cause. No consistent chromosome anomaly was found. An autosomal dominant mutation, either as submicroscopic chromosome deletion or duplication, or a point mutation seems the most likely explanation.

The Rubinstein-Taybi syndrome is a condition characterized by mental retardation, typical facial changes and broad thumbs and big toes. The cause is unknown; almost all cases are sporadic. We describe a mother and son with Rubinstein-Taybi syndrome. Literature search documented at least 413 cases with 558 sibs. An affected offspring has occurred at least twice, possibly six times. In 45 yet undescribed Dutch cases no recurrence was found in 94 sibs. A submicroscopic chromosome deletion seems the most probable explanation, but other alternatives may be possible.