Chapter 248

## Abstract

1. The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with a characteristic face, broad thumbs, broad big toes, and mental retardation as its major clinical hallmarks. RTS is generally a de novo-occurring autosomal dominant trait. The empirical recurrence risk for a couple with a previous child with RTS is as low as 0.1 percent. If, however, a person with RTS is able to reproduce, the recurrence risk could be as high as 50 percent. Birth prevalence is 1 in 100,000 to 125,000. RTS has been described in populations of many different ancestries, but the number of reports on non-Caucasian patients is low.

2. The main clinical features of the syndrome are abnormalities of the face, thumbs, and big toes, as well as growth and mental retardation. The facial appearance is striking: microcephaly, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum extending below the alae, highly arched palate, and mild micrognathia. Broad thumbs and broad big toes are present in almost all cases. Terminal broadening of the phalanges of the fingers, persistent fetal pads, clinodactyly of the fifth finger, overlapping of the toes, and angulation deformities of the thumbs and halluces can also be present. There is a marked growth retardation with poor weight gain during infancy, often replaced by being overweight in later childhood. Global mental deficiency is characteristic with an average IQ between 35 and 50. Short attention span, poor coordination, and sudden mood changes characterize the behavior of RTS patients. Other findings may include eye anomalies (nasolacrimal duct obstruction, ptosis of eyelids, congenital or juvenile glaucoma, and refractive errors), specific dental anomalies (talon cusps of the permanent incisors), a variety of congenital heart defects, and skin anomalies (supernumerary nipples, nevus flammeus, hirsutism, and keloid formation). The clinical history often shows feeding problems and recurrent conjunctivitis in the neonatal period, respiratory problems in the first decade, and life-long constipation. In general, RTS patients are in good health. Although an increased risk for different types of tumors is known, life expectancy seems to be normal.

3. The diagnosis is based on the clinical presentation. Combined cytogenetic and molecular investigations of the CREB-binding protein (CBP) gene area on chromosome 16p13.3 can confirm the diagnosis in 15 to 20 percent of the cases. Gross chromosomal rearrangements such as translocations and inversions are rarely found, whereas microdeletions occur in approximately 10 percent of cases. Point mutations in the CBP gene leading to premature translation-termination are reported as well. Heterogeneity is expected, but no reports on involvement of other genes have yet been published.

4. The CREB-binding protein functions as a transcriptional cofactor by forming a physical bridge between the different components of the transcription machinery. It also functions as a potent histone acetyltransferase, making the DNA accessible to transcription factors. Furthermore, it is a mediator of different signaling pathways and participates in basic cellular functions such as DNA repair, cell growth, cell differentiation, apoptosis, and tumor suppression. CBP is at the center of multiple signal transduction pathways and thereby regulates the expression of many genes.

5. Animal models and biochemical evidence suggest that RTS is caused by haploinsufficiency of CBP during fetal development. The exact developmental pathways affected by reduced levels of CBP are unknown. Until the in vivo functionality of CBP is better defined, there is no available treatment for RTS.

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