Definition

Rubinstein-Taybi syndrome (RSTS1, OMIM #180849; RSTS2, OMIM #613634) is a genetic disease caused by mutations in the CREBBP or EP300 genes. It is identified by characteristic facies, broad and often angled thumbs and big toes, dwarfism, and intellectual impairment.

Key Data

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Synonym Synonym Broad thumbs-hallux syndrome
Genes CREBBP (RSTS1): 40-50% of cases
EP300 (RSTS2): 3-8% of cases
Gene products CREB-binding protein (CREBBP)
Histone acetyltransferase p300 (EP300)
Function Histone methyltransferases functioning as a transcription factor
Heredity Autosomal dominant, but usually de novo mutations
Prevalence Incidence of 1:100.000-1:125.000
Genotype-phenotype correlation
  • Mosaic microdeletions in CREBBP lead to a milder phenotype than non-mosaic microdeletions.
  • Microduplications in CREBBP lead to a phenotype with mild to moderate intellectual impairment, normal growth, characteristic facies, slightly pronounced changes to the extremities, and various other symptoms.
  • The phenotype of individuals with EP300 mutations is generally milder: a number of affected individuals exhibit normally developed hands and feet. Intellectual development usually ranges between a normal IQ and moderate impairment.
Penetrance Unknown
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Diagnosis

Clinical Diagnostic Criteria

The clinical diagnosis of “Rubinstein-Taybi syndrome” is made based on the following findings:

  • Craniofacial appearance

    • Drooping palpebral fissures
    • Low-lying nose bridge
    • High palate
    • Grimacing laugh
    • Dens evaginatus, usually lingual at the remaining incisors of the maxilla
  • Broad, often angled thumbs and toes

  • Distally broad fingers

  • Maldescensus testis in male RSTS patients

  • Structural changes in the urogenital tract

  • Congenital heart diseases

  • Dwarfism during adulthood

  • Obesity during childhood and adolescence

  • Intellectual impairment (IQ between 25 and 79)

Genetic Diagnostics

In addition to the clinical diagnosis, the diagnosis of “Rubinstein-Taybi syndrome” is confirmed by the detection of a heterozygous germline mutation in the CREBBP gene through sequence analysis or deletion/duplication analysis. If no mutation is found, a sequence or deletion/duplication analysis of the EP300 gene should follow.

Differential Diagnoses

  • FGFR-associated craniosynostosis syndromes

  • Saethre-Chotzen syndrome

  • Greig cephalopolysyndactyly syndrome

  • Brachydactyly type D

  • Floating-Harbor syndrome

  • Keipert syndrome

Clinical Presentation

Children with Rubinstein-Taybi syndrome are usually identified at birth or in infancy due to the striking facies and the characteristic changes affecting the hands and feet. During infancy and early childhood, respiratory difficulties, feeding problems, lack of weight gain, recurring infections, and severe constipation may occur.

Symptoms can affect different organ systems and regions:

Craniofacial

Drooping palpebral fissures, low-lying nose bridge, high palate, grimacing laugh

Neurological

Craniospinal abnormalities and changes in the area of the posterior cranial fossa (Chiari malformation, syringomyelia, os odontoideum, and cervical bone marrow compression)

Eyes

Strabismus, refraction abnormalities, ptosis, obstruction of the nasolacrimal duct, cataract, coloboma, nystagmus, glaucoma, changes in the cornea, and retinal dysfunction

Cardiac

Around one third of RSTS patients have a congenital heart disease.

Urogenital

Renal changes are very common.
Maldescensus testis is present in nearly all male RSTS patients.

Skeletal

Broad, often angled thumbs and toes, distally broad fingers, dislocated patella, hypermobility of the joints, scoliosis, Perthes disease, slipped epiphysis at the femoral head, and changes in the cervical spine

Sleep apnea

Obstructive sleep apnea due to the combination of a narrow palate, micrognathia, muscular hypotension, obesity, and mild laryngeal wall collapse

Skin

Small keloids, pilomatrixomas

Teeth

Crowded teeth, malocclusion, multiple cavities, hypodontia, hyperdontia, natal teeth, and dens evaginatus (usually lingual at the remaining incisors of the maxilla)

Tumors

The following tumors have been described so far as part of RSTS: hepatoblastoma, ovarian and endometrial carcinoma, meningioma, pilomatrixoma, rhabdomyosarcoma, pheochromocytoma, neuroblastoma, medulloblastoma, oligodendroglioma, leiomyosarcoma, seminoma, odontoma, choristoma, and leukemia

Growth

Normal prenatal growth. During infancy, the parameters for growth, weight, and head circumference fall below the 5th percentile.
The average body height is 153 cm in men and 147 cm in women.
Boys often become obese during childhood and girls in adolescence.

Intellect

Developmental delay in motor, psychosocial, and speech areas. The IQ is between 25 and 79.

Behavior

Short attention span, low tolerance for noise and crowds, impulsiveness, and moodiness are frequently observed. In addition, attention deficit problems, hyperactivity, and self-injurious, aggressive, or autistic behavior may occur.

Therapeutic Considerations

In light of the extensive array of potential presentations, therapy should always be symptom-orientated and interdisciplinary, with the involvement of the corresponding specialist disciplines.

Surveillance Recommendations

Surveillance Recommendations

The following examinations should be conducted for patients with Rubinstein-Taybi syndrome for the purpose of early detection:

  • Close monitoring of body height, especially during the first year of life

  • Annual ophthalmological examination

  • Annual ENT examination, more frequently following multiple cases of otitis

  • Regular examinations to check for cardiac or renal changes

  • Regular dental examinations

If any anomalies are detected, additional examinations should be conducted as needed and the patient referred to the appropriate specialists.

Patients should be made aware of their moderately increased risk of cancer. Specific cancer surveillance is not recommended.

Additional Information

Open Clinical Trials / Registries

There are currently no ongoing clinical trials/registries for patients with Rubinstein-Taybi syndrome that we can recommend to you for more information.

Support Groups