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Rubinstein-Taybi syndrome (RSTS) is an extremely rare autosomal dominant genetic disorder characterised by:
- Dysmorphic facial features.
- Broad thumbs and first toes.
- Intellectual disability.
- Postnatal growth restriction.
It was first described in 1963 by Rubinstein and Taybi.
In the past the diagnosis was made based on clinical and radiological features. The genetic basis was first identified in 1991 when a new reciprocal translocation with break points in chromosomal region 16p13.3 was discovered in some patients. Subsequently the genes involved in many of the cases have been identified.
Epidemiology and genetics
- Incidence is about 1 case per 100,000 live births.
- Although inheritance is autosomal dominant most cases are sporadic resulting from new mutations with no history of any family members being affected.
- The majority of individuals reported to have RSTS are of European origin although some black and Asian cases have been seen. Whether this is because of a lower incidence in non-white populations or other factors is not known.
- Two genes which are currently known to be associated with RSTS are CREBBP and EP300. Pathogenic variants of CREBBP gene account for about 50-60% of cases and pathogenic variants of EP300 for another 5-8% of cases. In the remaining cases the responsible gene is not identified.
- If the parents are clinically unaffected the empirical recurrence risk in siblings of a child with RSTS is less than 1%. Individuals with RSTS rarely have children and their chance of having an affected offspring is 50%.
- Weight and length are normal at birth but growth is slow in infancy and childhood with the mean final height significantly less than average. Specific growth charts for monitoring growth in individuals with RSTS have now been developed.
- Facial features: low frontal hairline, arched thick eyebrows, downslanting palpebral fissures, prominent beaked nose with columella below the alae nasi, low-set/malformed ears, arched palate, mild micrognathia, dental anomalies and atypical smile with nearly completely closed eyes.
- Digital abnormalities: broad thumbs and great toes and clinodactyly of fifth finger.
- Skeletal abnormalities: abducted thumbs, vertebral anomalies, ligamentous laxity and severe prolonged aseptic inflammation of femoral head.
- Complex neuro-radiological issues including dysgenesis of corpus callosum, Chiari type 1 malformation, Dandy-Walker malformation and hydrocephalus and tethered cord have been reported.
- Cardiovascular abnormalities occur in a third of individuals and are usually isolated septal defects or patent ductus arteriosus; however, more complex conditions such as tricuspid atresia and pulmonary atresia have also been reported.
- Ocular abnormalities occur in the majority (84%) of patients and include glaucoma, strabismus, cataract, refractive errors, colobomata and anterior segment dysgenesis.
- Renal malformations and cryptorchidism.
- Developmental delay and learning difficulty is common and one study reported an average IQ of 39.
- Behavioural phenotype of children with RSTS is described as friendly and having good social contacts. However, short attention span and hyperactivity can be present and, during adolescence, anxiety, mood instability and aggressive behaviour can emerge.
- Recurrent respiratory tract infections occur in up to 75% of individuals with RSTS and are thought to be because of associated immune deficiency.
- Skin abnormalities, such as hirsutism, naevus flammeus on forehead and keloid formation.
Other similar syndromes to consider are:
- Pfeiffer's and Apert's syndromes.
- Saethre-Chotzen syndrome.
- Greig's cephalo-polysyndactyly syndrome.
- Floating-Harbor syndrome.
- Diagnosis of RSTS is primarily clinical. When the diagnosis is in question or features are atypical or severe, genetic testing needs to be undertaken.
- Chromosome abnormalities are occasionally seen on routine cytogenetic testing but genetic diagnosis requires testing for abnormalities of the two genes known to be associated with RSTS.
- Sequence analysis of CREBBP gene should be done first, followed by duplication/deletion analysis if no pathogenic variant is found. If this does not confirm diagnosis, similar testing of EP300 gene can be done.
- The wide spectrum of clinical manifestations requires disease management tailored to the problems of each patient.
- A comprehensive management plan based on the principle of regular multi-system evaluation and intervention has been proposed. This includes regular audiological, ophthalmological and orthopaedic evaluation, as well as echocardiogram and renal ultrasound at the time of diagnosis.
- In the first year of life specific attention needs to be given to feeding problems, constipation, lacrimal duct stenosis, congenital heart defects and glaucoma.
- Physiotherapy, speech therapy and special education are all required.
- Families of affected children need a great deal of support and all management intervention must be carefully co-ordinated and periodically reviewed.
- The survival rate is good, with frequent reports of survival to adulthood.
- Affected children have developmental delay, growth restriction and feeding difficulties.
- Respiratory tract infections and complications from congenital heart disease are primary causes of morbidity and mortality in infancy.
- Individuals with RSTS have an increased risk of developing malignancies, including brain tumours and haematological malignancies.
Further reading and references
; Online Mendelian Inheritance in Man (OMIM)
; Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management. Ital J Pediatr. 2015 Jan 2041:4. doi: 10.1186/s13052-015-0110-1.
Rubinstein JH, Taybi H; Broad thumbs and toes and facial abnormalities. Am J Dis Child 1963 105: 588-608.
; Gene Reviews
; Rubinstein-Taybi syndrome: clinical and molecular overview. Expert Rev Mol Med. 2007 Aug 209(23):1-16.
; Genetics Home Reference
; Growth charts for individuals with Rubinstein-Taybi syndrome. Am J Med Genet A. 2014 Sep164A(9):2300-9. doi: 10.1002/ajmg.a.36654. Epub 2014 Jul 2.
; Tricuspid atresia and pulmonary atresia in a child with Rubinstein-Taybi syndrome. Ann Pediatr Cardiol. 2015 May-Aug8(2):157-60. doi: 10.4103/0974-2069.154151.
; Fluorescein angiography findings in a case of Rubinstein-Taybi syndrome. Clin Ophthalmol. 20126:1369-71. doi: 10.2147/OPTH.S31023. Epub 2012 Aug 22.
; Rubinstein-Taybi syndrome: Clinical profile of 11 patients and review of literature. Indian J Hum Genet. 2012 May18(2):161-6. doi: 10.4103/0971-6866.100751.
; Age-dependent change in behavioral feature in Rubinstein-Taybi syndrome. Congenit Anom (Kyoto). 2012 Jun52(2):82-6. doi: 10.1111/j.1741-4520.2012.00356.x.
; Rubinstein-Taybi syndrome: an immune deficiency as a cause for recurrent infections. Allergy Asthma Proc. 2006 May-Jun27(3):281-4.