Dermatologic Manifestations of Rubinstein-Taybi Syndrome 

Updated: Jun 20, 2018
Author: Zeljko P Mijuskovic, MD, PhD; Chief Editor: William D James, MD 

Overview

Background

In 1963, Rubinstein and Taybi first described Rubinstein-Taybi syndrome (RSTS) (Mendelian Inheritance in Man [MIM] #180849). Rubinstein-Taybi syndrome is a well-delineated malformation syndrome characterized by facial abnormalities, broad thumbs, broad great toes, short stature, and mental retardation.[1, 2, 3]

For additional information, see the article Rubinstein-Taybi Syndrome.

Pathophysiology

The locus of Rubinstein-Taybi syndrome is located on band 16p13.3, which includes a gene encoding a binding protein for cyclic adenosine monophosphate–response element binding protein (CBP) (CREBBP or CBP gene) that is responsible for the phenotype of Rubinstein-Taybi syndrome. CBP spans approximately 150 kb with 31 exons, and its cDNA is 9 kb in length.[4, 5, 6, 7] Genetically based growth retardation and feeding difficulties are the main problems in early life; however, respiratory tract infections and complications from congenital heart disease are primary causes of morbidity and mortality in infancy.

Milder variants of Rubinstein-Taybi syndrome have been reported, with less retardation and more subtle clinical features. These patients have been referred to as having "incomplete” Rubinstein-Taybi syndrome.

Etiology

Mutations in two genes, CBP (CREBBP) and EP300, have been identified in affected individuals.[8, 9]

CBP and EP300 are ubiquitously expressed homologous proteins that act as transcriptional co-activators. Both genes are highly conserved, and their proteins are thought to have 2 functions: (1) formation of a bridge or scaffold between the DNA-binding transcription factors and the RNA polymerase II complex and (2) serving as histone acetyltransferases that open the chromatin structure, a process essential for gene expression.[10] During organogenesis, CBP is expressed in specific cell types of the developing heart, vasculature, skin, lungs, and liver. Many of these tissues and organs are known to be affected in mutant mice lacking CBP and in patients with Rubinstein-Taybi syndrome.

Disruption of the human CBP gene, either by gross chromosomal rearrangements or by point mutations, leads to Rubinstein-Taybi syndrome. Translocations and inversions involving band 16p13.3 form the minority of CBP mutations, while microdeletions occur more frequently (approximately 10%). Point mutations and small deletions or insertions of the CBP and EP300 genes 3,18,19, as well as deletions and duplications 41000 bp in length to megabases, have been shown to lead to Rubinstein-Taybi syndrome.[10] Blough et al[11] reported that no phenotypic differences were observed among patients with partial deletion, complete deletion, and nondeletion, supporting a haploinsufficiency model for Rubinstein-Taybi syndrome.

Roelfsema et al[12] reported EP300 gene mutations in 3 (3.3%) of 92 patients with either true Rubinstein-Taybi syndrome or different syndromes resembling Rubinstein-Taybi syndrome. The EP300 gene on band 22q13 encodes a protein, p300, that is highly similar to CREBBP. At present, the cause of Rubinstein-Taybi syndrome remains unknown in approximately half the patients. Both CBP and EP300 interact with several cofactors (p/CAF, CITED1, CITED4), which can also be involved in Rubinstein-Taybi syndrome and would indicate further genetic heterogeneity.

Individuals reported with mutations in EP300 have a milder skeletal phenotype, lacking typical broadening and angulation of the thumb and hallux.

For both genes, a mutation database is available that also includes unpublished mutations, as follows:

  • CBP

  • EP300

Epidemiology

Frequency

The prevalence of Rubinstein-Taybi syndrome in the general population is approximately 1 case per 300,000 persons and is as high as 1 case per 10,000 live births. Cantani and Gagliesi[13] reported that Rubinstein-Taybi syndrome is not so rare and is present in approximately 1 in 600 patients seen in mental retardation clinics. Most cases of Rubinstein-Taybi syndrome are sporadic, although it has been reported in monozygotic twins. Families with more than 1 affected child are extremely rare.[14]

Race

Rubinstein-Taybi syndrome has no racial predilection.

Sex

Rubinstein-Taybi syndrome has no sexual predilection.

Age

The syndrome can often be recognized in the neonatal period by the typical abnormalities seen in the thumbs, the great toes, and the face.

Prognosis

The survival rate is good, with frequent reports of adult patients with Rubinstein-Taybi syndrome. Patients with Rubinstein-Taybi syndrome have an increased risk of developing malignancies, including brain tumors (meningioma, medulloblastoma) and hematologic malignancies (leukemia).[14, 15]  Genetically based growth retardation and feeding difficulties are the principal problems hindering the development of children. Respiratory tract infections and complications resulting from congenital heart disease are primary causes of morbidity and mortality in infancy. Milestones in patients with Rubinstein-Taybi syndrome are delayed.

Patient Education

The Web site Rubinstein-Taybi Syndrome is devoted to people with Rubinstein-Taybi syndrome and their families. Photographs of children and adults with Rubinstein-Taybi syndrome, Rubinstein-Taybi syndrome organizations around the world, and lists of books and other resources for families are available.

 

Presentation

History

Patients may present with the following:

  • Characteristic abnormalities of the head, the face, the eyes, and the skin

  • Distinctive abnormalities of the fingers and the toes

  • Developmental delays, growth retardation, speech delays, and/or mental retardation

  • Skeletal malformations

Physical Examination

Facial abnormalities are as follows (see images below list):

  • Hypoplastic maxilla with narrow palate (100%)

  • Prominent beaked nose (90%)

  • Antimongoloid palpebral fissures (88%)

  • Low-set/malformed ears (84%)

  • Strabismus (69%)

  • Large anterior fontanelle (41%)

  • Microcephaly (35%)

  • Small mouth

  • Crowded irregular teeth, high palate, thick upper lip, short upper lip, and protuberant lower lip

    Facial abnormalities (eg, hypoplastic maxilla, pro Facial abnormalities (eg, hypoplastic maxilla, prominent beaked nose, antimongoloid palpebral fissures) and broad thumbs in a child with Rubinstein-Taybi syndrome.
    Prominent beaked nose, low-set ears, and broad thu Prominent beaked nose, low-set ears, and broad thumbs in a child with Rubinstein-Taybi syndrome.

Digital abnormalities are as follows (see image below):

  • Broad great toes (100%)

  • Broad thumbs with radial angulation (87%)

  • Broad fingers (87%)

  • Persistent fetal finger pads (31%)

  • Duplicated longitudinal bracketed epiphysis (kissing delta phalanx)[16]

  • Syndactyly, polydactyly, and ulnar deviation of the thumb

    Broad great toes in a child with Rubinstein-Taybi Broad great toes in a child with Rubinstein-Taybi syndrome.

Ocular abnormalities are as follows[17] :

  • Strabismus (60-71%)

  • Nasolacrimal duct problems (38-47%)

  • Congenital or juvenile glaucoma

  • Retinal abnormalities

  • Ptosis (29-32%)

  • Refractive errors (41-56%)

  • Macrocornea, microphthalmos, colobomas (9-11%), congenital cataract, optic nerve atrophy, and corneal keloid

Abnormalities of growth and development are as follows:

  • Mental retardation, with an intelligence quotient (IQ) of 30-79; IQ of less than 50 found in more than 50% of patients

  • Speech difficulties (90%)

  • Hypotonia (67%)

  • Growth retardation (postnatal-onset growth deficiency; average height of men is 153 cm [60 in], and average height of women is 147 cm [58 in], more frequently in patients with no CREBBP mutation)[18]

  • Feeding problems (85%) and echolalia

Skeletal abnormalities are as follows:

  • Retarded osseous maturation (49%)

  • Vertebral and sternal abnormalities (including instability of C1-C2)

  • Patellar dislocation

  • Patellofemoral instability

  • Fourth cuneiform bones[19]

  • Joint hypermobility

Skin findings are as follows:

  • Hirsutism (75%)

  • Capillary nevus of the forehead or the nape (>50%)

  • Keloid formation (4.87%)[20]

  • Multiple pilomatricomas,[21] piebaldism, long eye lashes, epidermal nevus, keratosis pilaris atrophicans faciei,[22] and striate palmoplantar keratoderma[23]

Cardiovascular system findings are as follows[24] :

  • Cardiac anomalies (32.6%)

  • ECG abnormalities (30%)

  • Cardiac arrhythmias with the use of succinylcholine

  • Ventricular septal defect and patent ductus arteriosus (both are most common)

  • Atrial septal defect, coarctation of the aorta, pulmonary artery stenosis, bicuspid aortic valve, hypoplastic left-sided heart, and conduction abnormalities

Other conditions are as follows:

  • Cryptorchidism (78-100% of males)

  • Gastroesophageal reflux (68%)

  • Constipation (40-74%)

  • Laryngeal wall collapsibility (may cause sleeping problems and difficulty during anesthesia)

  • Insomnia (glossoptosis can cause sleep apnea)

  • Mood disorders and obsessive compulsive disorder

  • Abnormal pulmonary lobulation, bilateral vesicoureteral reflux, micropenis, renal agenesis, pachygyria,[14] polysplenia, thymic hypoplasia, megacolon, multiple meningiomas,[25] congenital tracheal stenosis, epilepsy, hepatic hemangioma and congenital hypothyroidism

Complications

Cardiac arrhythmias can result if succinylcholine is administered. Sleeping problems include insomnia; glossoptosis can cause sleep apnea. Laryngeal wall collapsibility may cause sleeping problems and difficulty during anesthesia.

 

DDx

Diagnostic Considerations

Also consider the following:

  • Faciodigitogenital syndrome (Aarskog syndrome)
  • Greig syndrome
  • Larsen syndrome
  • Pfeiffer syndrome
  • Saethre-Chotzen syndrome
  • Simpson-Golabi-Behmel syndrome
  • Weaver syndrome
 

Workup

Imaging Studies

The types of imaging studies performed depend on the clinical manifestations of the patient. For example, a patient with skeletal abnormalities requires further radiologic investigations, such as CT scanning and MRI.

Other Tests

Note the following:

  • Chromosomal karyotype analysis - To investigate for the presence of structural abnormalities

  • Fluorescence in situ hybridization - To detect microdeletions of the CBP gene on band 16p13

  • Mutation analysis of the CBP gene

Procedures

Note the following:

  • Electrocardiogram, echocardiogram, and examination by a pediatric cardiologist[26]

  • Radiologic investigations for patients with skeletal abnormalities

  • Renal ultrasonography and consideration of a voiding cystourethrogram

  • Hearing evaluation

  • Neurologic evaluation for patients with a seizure disorder

 

Treatment

Medical Care

The wide spectrum of clinical manifestations requires disease management tailored to the problems of each patient. Physical therapy, speech and feeding therapy, and special education are important supportive measures in infancy.

Surgical Care

Individualize surgical treatment based on findings in the patient. For example, a patient with a congenital heart defect may need cardiothoracic intervention.

Consultations

Prenatal testing for at-risk pregnancies is possible if the disease-causing CBP mutation or deletion in the family is known.

Consult a cardiologist for evaluation of congenital heart disease.

Consult a neurologist for evaluation of EEG and other neurologic abnormalities.

Consult an ophthalmologist for evaluation of eye abnormalities.

Consult an orthopedist for evaluation of skeletal abnormalities.

Consult a pediatric dentist every 6 months beginning at age 1 year.[26]

Long-Term Monitoring

Physical therapy, speech and feeding therapy, and special education are important supportive therapies in infancy.