Dermatologic Manifestations of Rubinstein-Taybi Syndrome Clinical Presentation

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

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, short upper lip, and protuberant lower lipFacial 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 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)^[3]
• Syndactyly, polydactyly, and ulnar deviation of the thumbBroad great toes in a child with Rubinstein-Taybi syndrome.

Ocular abnormalities are as follows^[4] :

• 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)^[5]
• 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^[6]
• Joint hypermobility

Skin findings are as follows:

• Hirsutism (75%)
• Capillary nevus of the forehead or the nape (>50%)
• Keloid formation (4.87%)^[7]
• Multiple pilomatricomas,^[8] piebaldism, epidermal nevus, keratosis pilaris atrophicans faciei,^[9] and striate palmoplantar keratoderma^[10]

Cardiovascular system findings are as follows^[11] :

• 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, renal agenesis, polysplenia, thymic hypoplasia, megacolon, multiple meningiomas,^[12] congenital tracheal stenosis, epilepsy, hepatic hemangioma and congenital hypothyroidism

Mutations in 2 genes, CBP (CREBBP) and EP300, have been identified in affected individuals.

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.^[13] 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.^[13] Blough et al^[14] 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^[15] 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