Rubinstein-Taybi Syndrome – 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.
Synonym:
Broad Thumbs-Hallux Syndrome
Gene:
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 that act as transcription factors
Pattern of inheritance:
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
Rubinstein-Taybi Syndrome – 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, “Rubinstein-Taybi syndrome” diagnosis is confirmed by detecting 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 noticed at birth or in infancy due to the distinctive facies and characteristic changes in the hands and feet. In infancy and early childhood, respiratory difficulties, feeding problems, poor weight gain, recurrent infections, and severe constipation may occur.
Symptoms can affect various organ systems and areas:
Craniofacial
Drooping palpebral fissures, low 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, refractive anomalies, ptosis, obstruction of the nasolacrimal duct, cataract, coloboma, nystagmus, glaucoma, changes in the cornea, and retinal dysfunction
Cardial
Around a 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
To date, the following tumors have been described in the context of RSTS: Hepatoblastoma, ovarian and endometrial carcinoma, meningioma, pilomatrixoma, rhabdomyosarcoma, pheochromocytoma, neuroblastoma, medulloblastoma, oligodendroglioma, leiomyosarcoma, seminoma, odontoma, choristoma and leukemias.
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.
Special Features of Treatment
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.
Diagnosis of Rubinstein-Taybi Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Rubinstein-Taybi Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
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 should be referred to the appropriate specialists.
Patients should be made aware of their moderately increased risk of cancer. Specific cancer surveillance is not recommended.
