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Rubinstein-Taybi syndrome is a rare malformation syndrome characterized by congenital anomalies (microcephaly, specific facial characteristics, broad thumbs and halluces and postnatal growth retardation), short stature, intellectual disability and behavioural characteristics.
Birth prevalence is estimated at around 1/ 100,000 to 125,000.
Facial features, which become more prominent with age, include highly arched eyebrows, long eyelashes, downslanting palpebral fissures, convex nasal ridge, low hanging columella, highly arched palate and micrognathia. Talon cusps are very frequent on the permanent incisors. An unusual smile with almost complete closure of the eyes is present in most cases. Other physical findings may include eye anomalies (nasolacrimal duct obstruction, congenital glaucoma, refractive errors), a variety of congenital heart defects (e.g. ventricular and atrial septal defect, patent ductus arteriosus), joint hypermobility, and skin anomalies (in particular keloid formation). Feeding difficulties are frequently observed in the neonatal period, and respiratory infections are very common in infancy and childhood. Constipation is generally a life-long problem, and patients may become overweight during late childhood or early puberty. As children, patients have a marked ability to establish excellent social contacts. In adulthood, sudden mood changes and obsessive-compulsive behavior become gradually more frequent. An increased risk of tumors (mainly leukemia in childhood and meningeoma in adulthood) has been observed.
Causes of Rubinstein-Taybi syndrome include: microdeletion of chromosome 16p13.3, CREB-binding protein mutations (CREBBP, 16p13.3) and E1A-binding protein p300 mutations (EP300, 22q13.2). CREBBP and EP300 show a very high degree of homology and both play important roles as global transcriptional coactivators. The exact pathogenesis of the syndrome remains uncertain. There is no significant genotype-phenotype correlation, except possibly in the case of individuals with a EP300 mutation that seem to have a higher level of functioning and less marked distal limb malformations.
The diagnosis is in essence based on clinical examination. A cytogenetic or molecular abnormality can be detected in about 65% of patients.
The syndrome can sometimes be difficult to differentiate from Saethre-Chotzen syndrome, Floating Harbor syndrome and Cornelia de Lange syndrome (see these terms).
If a cytogenetic or molecular abnormality is found in the affected child, reliable prenatal diagnosis is possible during future pregnancies through chorionic villus biopsy. Prenatal ultrasound only rarely allows a reliable diagnosis.
The syndrome is almost always sporadic, most cases resulting from de novo mutations. The recurrence risk for parents of an index case is low (0.1%). There are no reports of affected children of siblings of an index case but there have been instances of germline mosaicism. The chance of patients having an affected child may be as high as 50%, as the transmission is autosomal dominant.
Management and treatment
Patient management is mainly symptomatic. Specialised educational programs are required, with early emphasis on psychomotor development and speech therapy.
Life expectancy does not seem to be altered, except in children with complex cardiac defects. Malignancies and respiratory infections are the most common causes of death.