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Rubinstein-Taybi syndrome

This is part of Rare diseases.

Diagnosis: Rubinstein-Taybi syndrome

Synonyms: --

Innehåll


Publication date: 2011-11-09
Version: 2.0

ICD 10 code

Q87.2D

The disease

Rubinstein-Taybi syndrome is associated with short stature, intellectual disability and a characteristic appearance. It is also frequently distinguished by the malformation of internal organs.

The syndrome was described first in 1957 by Greek orthopaedic surgeons J P Michail, J Matsoukas och S Theodouru. A more thorough study of seven children was made in 1963 by American physician Jack Herbert Rubinstein and Iranian-American physician Hooshang Taybi, who gave their names to the syndrome.

Occurrence

It is estimated that one or two neonates out of every 100,000 have Rubinstein-Taybi syndrome. In Sweden, it is estimated that one or two children with the syndrome are born every year. Approximately fifty people in Sweden have been diagnosed with the condition.

Cause

In most cases the cause is a mutation in a gene on the short arm of chromosome 16 (16p13.3). The gene is known as CBP or CREBBP and it controls the production of (codes for) a protein named CPB (CREB-binding protein) or cyclic AMP-binding protein.

The defect is either a deletion with partial or complete loss of the gene, or a point mutation. The latter means that a base pair substitution or loss of a base pair has occurred in a coding nucleic acid in the gene. The result is a partial or complete loss of function in gene CBP. Approximately 50 per cent of cases are caused by a point mutation, while ten to fifteen per cent are the result of the deletion of the entire gene. In approximately three per cent of children affected, the syndrome is caused by a mutation in the EP300 gene situated on the long arm of chromosome 22 (22q13). EP300 codes for the histone acetyltransferase protein.

These two genes regulate the activity of other genes, which in turn control the development of various organs in the foetal stage. Point mutations or deletions in either gene inhibit their regulatory roles in foetal organ development, to a greater or lesser degree. The end result is the various disabilities and characteristic signs which distinguish Rubinstein-Taybi syndrome.

Heredity

In most people Rubinstein-Taybis syndrome is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children. However, it is unusual for people with the syndrome to become parents.

In isolated cases an inherited form is identified in which one of the parents is a carrier of a sub-microscopic microdeletion (meaning that a very small chromosome fragment is missing) or a point mutation in the CREBBP gene. Several forms of Rubinsten-Taybi syndrome, manifesting different symptoms, can occur within the same family.

Symptoms

Newborns with the syndrome have short stature and low birth weight, and most have a characteristic appearance. Thumbs and big toes are broad and often point outwards, and the little finger is short and crooked. These characteristics mean that the syndrome may already be suspected at birth. Sucking and swallowing reflexes are weak, and vomiting is a common problem. These symptoms cause feeding difficulties and the children fail to thrive. Constipation may also be a problem.

Breathing difficulties, allergic reactions and respiratory tract infections are common. Owing to middle-ear infections, hearing is sometimes mildly impaired. During the first years in particular, children with the syndrome may be subject to pulmonary infections as they breathe food into the windpipe (aspiration).

Constriction in the upper respiratory passages may cause recurrent episodes of sleep apnoea (abnormal pauses in breathing during sleep).

Motor development is delayed. Balance is poor and the gait clumsy and stiff. Children with the syndrome usually start to walk at between eighteen months and two years of age. Many have hypermobility of the joints, concave chest, scoliosis (abnormal curvature of the spine) and lordosis (exaggerated curvature of the lower spine).

Malformations of the internal organs are common. Approximately 50 per cent of individuals with the syndrome have urinary tract defects, and in some boys the urethra opens on the underside of the penis (hypospadias). In boys, the testicles usually fail to descend into the scrotum (cryptorchidism). Kidney function may be defective. One kidney may be absent or the child may have duplex kidneys. An abnormal flow of urine from the bladder up into the ureters (vesicoureteral refluxis) is characteristic of the syndrome and gives an increased risk of urinary infections.

Some children with the syndrome have a tethered spinal cord, which during the child’s first months is fixed in the spinal column. When the child grows, nerve tissue becomes stretched, leading in some cases to a gradual deterioration of muscles, bladder and bowels.

One third of children with Rubinstein-Taybi syndrome have a congenital heart defect. The most common anomaly is a hole in the wall separating the chambers of the heart (ventricle septal defect), or an open connection between the left pulmonary artery and the aorta (persistent ductus arteriosus). Some children have an opening in the wall separating the right and left atria (atrial septal defect), an abnormal narrowing of the aorta (aortic coarctation), or a defective pulmonary valve, obstructing the blood flow from the right ventricle to the lungs (pulmonary stenosis). In some cases the left side of the heart is underdeveloped (hypoplastic). Life expectancy may be reduced in those people with Rubinstein-Taybi syndrome who also have congenital heart defects or are particularly susceptible to infection.

More than two thirds of children with the syndrome have eye problems, including squinting (strabismus), refractive errors, drooping eyelids (ptosis) or narrow tear ducts.

Everyone with Rubinstein-Taybi syndrome has an intellectual disability, usually severe. Severe concentration problems, the reduced ability to sustain an activity over a period of time and hyperactivity are also common. As their social interaction skills are poor, these children often withdraw from company. Hypersensitivity to sound is common.

The facial features, including downward-slanting eyes (palpebral fissures), prominent eyebrows and lashes, become more distinct as the child becomes older. The jaws are narrow and underdeveloped. The palate is usually high and narrow and the teeth crowded. A few teeth may have abnormally shaped anterior sides and surface protrusions (talon cusp) that sometimes affect the bite.

Abnormally increased hair growth (hirsutism) is common.

Diagnosis

The diagnosis is based on a combination of various symptoms and characteristic physical features. Virtually all Rubinstein-Taybi patients have broad thumbs and big toes with double phalanx bones. This can be confirmed by an X-ray which often also reveals malformations of the vertebrae, sternum and ribs. Bone maturation is often delayed in comparison with healthy children.

DNA analysis can be used to confirm the diagnosis in more than 50 per cent of all cases. Foetal diagnosis, and on occasion embryo diagnosis, are possible if the mutation in the family has been identified. Genetic counselling should be offered when the diagnosis is made.

Treatment/interventions

There is currently no cure for the disorder, and efforts are directed at relieving symptoms. When the diagnosis is confirmed the child and family should be put in contact with appropriate specialists as different organs may be affected. A paediatrician with a holistic view of the child’s situation should coordinate investigations and treatments.

Various treatments are available to control symptoms and much can be done to provide support and compensate as far as possible for disabilities.

As approximately one third of all individuals with the syndrome have a congenital heart defect, it is important that these children are examined by a paediatric cardiologist. If a heart defect is found, the child should be monitored regularly, either by a cardiologist or the physician who usually sees the child. Heart defects are usually, but not always, corrected through surgical intervention.

An ophthalmologist should examine the child at a very early stage so that eye problems can be dealt with. Regular eye and vision check-ups are important so that any changes to the eyes which affect vision, may be noted. Squinting is treated by covering the normal eye with a patch in order to train the affected eye.

In cases of recurring infections, levels of immunoglobulins and antibodies indicating exposure to different infectious agents and/or vaccinations, should be checked. An ENT (Ear, Nose and Throat) specialist should examine the child if there are recurrent ear infections, and many children with the syndrome require the insertion of a grommet (a small plastic tube) through the eardrum to release fluid. Even children without recurring ear infections should have their hearing checked regularly by a doctor. Mild hearing loss as a result of fluid in the middle ear can be treated by a grommet. Devices to improve hearing, such as hearing aids, may be required and should be tried out at an early stage.

The child’s back should be examined by a paediatric orthopaedic surgeon. The vertebral column should be X-rayed to reveal any abnormalities, such as part of a vertebra being missing. A surgical corset can be used to treat the early stages of scoliosis, but surgery may also be required.

A tethered spinal cord can be untethered in a neurosurgical procedure, so alleviating any gradual deterioration in the child’s condition.

Abnormally broad big toes, and outward-pointing thumbs require surgical intervention.

All children with the syndrome should also undergo an examination of the kidneys as structural anomalies in these organs increase the risk of urinary tract infections. Renal anomalies sometimes require surgical intervention. Boys whose testicles have not descended into the scrotum, need corrective surgery.

Owing to the risk of anaesthesia complications, patients with Rubinstein-Taybi syndrome should be examined by an anaesthetist before planned surgery. As there is a high risk of complications associated with tracheal intubation (when a tube is placed in the throat to help breathing during surgery), magnetic resonance imaging of the cervical spine is always recommended before surgery to reveal any pressure on the spinal cord. Certain complications, such as irregular heartbeat, may affect children with heart defects when they are under anaesthetic.

Optimal prophylactic dental care is advisable, as many children with the syndrome find it difficult to cooperate in brushing their teeth or dental treatment. Specialist treatment from a paediatric dentist should gradually accustom the child to regular visits. Dental braces are often necessary. During dental treatment which may cause bleeding, people with heart defects may sometimes require prior treatment with antibiotics on the advice of a cardiologist. This is because bacteria in the oral cavity can sometimes cause infections affecting the heart (endocarditis).

In order to ensure that children with sucking and eating difficulties are well nourished, the parents may need help from a nutrition team, including professionals such as a dietician and a speech therapist. A dietician can give advice on suitable food in cases of severe constipation, which can be a frequent problem. In such cases the child requires increased amounts of dietary fibre and large helpings of fruit and vegetables. Plenty of fluid with meals, and juice between meals will also help maintain good bowel movement. If medication becomes essential, bulking agents which bind liquids and increase volume should be the first choice.

Early habilitation is essential to stimulate development and help compensate for functional limitations. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information on all available support offered in the community, as well as advice on adjustments to the home environment and other places where the child spends time. The child, parents and siblings should be offered support. The family may also need help coordinating interventions.

Communication skills vary among individuals, and it is important to implement early speech, language and communication training. Augmentative and alternative communication (AAC) should be offered at an early stage.

Motor stimulation and practice in all types of movement should be offered to give the child the preconditions to manage everyday activities on his or her own terms. Habilitation should make everyday life easier by helping with basic daily tasks such as eating, dressing and washing oneself as well as playing and spending time with peers, siblings and parents.

Adults with the syndrome may require continued habilitation and support, adapted to their individual, daily needs. They may, for example, need accommodation offering special services for the disabled and daily activities.

Practical advice

For babies who vomit easily, bottle-feeding becomes easier if the hole in the teat is on the side instead of in the middle.

National and regional resources in Sweden

The Swedish Centre for Children and Young People with Congenital Malformations and Syndromes, Uppsala University Children’s Hospital. Tel: +46 18 611 59 42, +46 18 611 30 90.

Resource personnel

Professor Göran Annerén, Department of Clinical Genetics, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 42, fax: +46 18 611 40 25, email: goran.anneren@igp.uu.se.

Senior Physician Britt-Marie Anderlid, Astrid Lindgren Children’s Hospital and Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Senior Physician Ann Nordgren, Department of Clinical Genetics, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 10.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year a number of adults with rare diseases also visits Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations

The Swedish Rubinstein-Taybi Association. Contact: Ann-Louise Magnusson, Saint Olofsvägen 1, SE-864 33 Matfors, Sweden. Tel: +46 60 225 17, email: jensm@telia.com or ann-louise.k@spray.se, www.rtssverige.se.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Gävlegatan 18 C, Stockholm. Mailing address: Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Stockholm. Mailing address: Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@riks.rbu.se, www.rbu.se.

Courses, exchanges of experience for personnel

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development (R&D)

--

Information material

An information leflet on Rubinstein-Taybi syndrome that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-3-24). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The Ågrenska National Competence Centre for Rare Diseases has published a newsletter on Rubinstein-Taybi syndrom, nr 368 (2010). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.

”Information om Sjaeldne Handicap, Rubinstein-Taybis syndrom” (in Danish). Order from: Center for Små Handicapgrupper, Bredgade 25 F, 5 sal, DK-1260 Copenhagen K, Denmark. Tel: +45 339 140 20, fax: +45 339 140 19, email: csh@csh.dk, www.csh.dk.

Information material on Rubinstein-Taybi syndrome from Frambu (in Norwegian). Order from: Frambu, Senter for sjeldne funksjonshemninger, Sandbakkveien 18, NO-1404 Siggerud, Norway.Tel: +47 64 85 60 00, fax: +47 64 85 60 99, email: info@frambu.no, www.frambu.no.

Leaflet nr 18 (In Norwegian only) from Frambu, Senter for sjeldne funksjonshemningar (2005). Order from: Frambu, Senter for sjeldne funksjonshemninger, Sandbakkveien 18, NO-1404 Siggerud, Norway.Tel: +47 64 85 60 00, fax: +47 64 85 60 99, email: info@frambu.no, www.frambu.no.

Literature

Bartsch, O., Kress, W., Kempf, O., Lechno, S., Haaf, T., Zechner, U. Inheritance and variable expression in Rubinstein-Taybi syndrome. Am. J. Med. Genet. 2010; 152A: 2254-2261.

Bartsch, O., Labonte, J., Albrecht, B., Wieczorek, D., Lechno, S., Zechner, U., Haaf, T. Two patients with EP300 mutations and facial dysmorphism different from the classic Rubinstein-Taybi syndrome. Am. J. Med. Genet. 2010 ; 152A: 181-184.

Berry AC. Rubinstein-Taybi syndrome. J Med Genet 1987; 24: 562-566.

Breuning MH, Dauwerse HG, Fugazza G, Saris JJ, Spruit L, Wijnen H et al. Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. Am J Hum Genet 1993; 52: 24954.

Cantani A, Gagliesi D. Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci 1998; 2: 81-87.

Coupry I, Roudaut C, Stef M, Delrue M-A, Marche M, Burgelin I et al. Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. J Med Genet 2002; 39: 415-421.

Galéra C, Taupiac E, Fraisse S, Naudion S, Toussaint E, Rooryck-Thambo C et al. Socio-behavioral characteristics of children with Rubinstein-Taybi syndrome. J Autism Dev Disorder 2009; 39: 1252-1260.

Hellings JA, Hossain S, Martin JK, Baratang RR. Psychopathology, GABA, and the Rubinstein-Taybi syndrome: A review and case study. Am J Med Genet 2002; 114: 190-195.

Hennekam RC, Tialnus M, Hamel BC, Voshart-van Heeren H, Mariman EC, van Beersum SE et al. Deletion at chromosome 16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects. Am J Hum Genet 1993; 52: 255-262.

Marangi G, Leuzzi V, Orteschi D, Grimaldi ME, Lecce R, Neri G et al. Duplication of the Rubinstein-Taybi region on 16p13.3 is associated with a distinctive phenotype. Am J Med Genet A 2008; 146: 2313-2317.

Michail J, Matsoukas J, Theodorou S. Pouce bot argue en forte abduction-extension et autres symptomes concomitants. Revue de chirurgie orthopédique et réparatrice de l’appareil locomoteur, Paris 1957; 43: 142-146.

Petrij F, Dauwerse HG, Blough RI, Giles RH, van der Smagt JJ, Wallerstein R et al. Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J Med Genet 2000; 37: 168-176.

Roelfsema JH, White SJ, Ariyurek Y, Bartholdi D, Niedrist D, Papadia F et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet 2005; 76: 572-580.

Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. American Journal of Diseases of Children, Chicago 1963; 105: 588.

Taine L, Goizet C, Wen ZQ, Petrij F, Breuning MH, Ayme S et al. Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome. Am J Med Genet 1998; 78: 267-270.

Wallerstein R, Anderson CE, Hay B, Gupta P, Gibas L, Ansari K et al. Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population. J Med Genet 1997; 34: 203-206.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: rubinstein-taybi syndrome

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles.) 
Search: rubinstein-taybi syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Emeritus Karl-Henrik Gustavson, The Rudebeck Laboratory, Uppsala University Hospital, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2011-11-09
Version: 2.0
Publication date of the Swedish version: 2011-08-10

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: + 46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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