Rubinstein-Taybi Syndrome 2

A number sign (#) is used with this entry because Rubinstein-Taybi syndrome-2 (RSTS2) is caused by heterozygous mutation in the EP300 gene (602700) on chromosome 22q13. Most, if not all, mutations occur de novo.

Description

Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The classic facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile (Rubinstein and Taybi, 1963; review by Hennekam, 2006).

About 50 to 70% of patients have RSTS1 due to mutation in the CREBBP gene (600140). RSTS2 is much less common, and about 3% of patients have mutations in the EP300 gene. RSTS2 appears to be associated with a milder phenotype than RSTS1. Patients with RSTS2 have less severe facial dysmorphism and better cognitive function, but may have more severe microcephaly and malformation of facial bone structures compared to those with RSTS1 (Bartsch et al., 2010).

For a discussion of genetic heterogeneity of Rubinstein-Taybi syndrome, see RSTS1 (180849).

Clinical Features

Roelfsema et al. (2005) reported 3 unrelated patients with RSTS2. The phenotypes were compatible with RSTS in most respects: all patients had heavy and arched eyebrows, long eyelashes, a prominent nose with long columella, and a pouting lower lip. However, only 1 patient had micrognathia, 1 had mildly downslanted palpebral fissures, and none had the grimacing smile. All had short broad thumbs and big toes, and square distal fingertips. The patients were identified from a larger cohort of 92 patients with a clinical diagnosis of RSTS.

Bartholdi et al. (2007) reported detailed clinical features of 4 RSTS patients with mutations in the EP300 gene; 3 of the patients had been reported by Roelfsema et al. (2005). The patients had the typical facial gestalt, malformation patterns, and mental and behavioral signs consistent with the syndrome, but 3 patients did not show the classic malformations on both hands and feet, which originally had been considered mandatory for the diagnosis. The authors concluded that clinical variability in RSTS may be due to genetic heterogeneity and emphasized that the diagnosis must be expanded to include individuals without broad thumbs or halluces.

Zimmermann et al. (2007) reported a female with a mild form of RSTS due to a de novo heterozygous mutation in the EP300 gene (602700.0006). She had microcephaly, beaked nose, narrow high-arched palate, and borderline intelligence (IQ of about 75). Bartsch et al. (2010) provided more detailed information on the patient reported by Zimmermann et al. (2007). At age 19, she had global developmental delay, but was able to work in a sheltered workshop after being schooled in special needs. She had marked mandibular retrognathism, requiring surgical correction. Other features included mild myopia, bilateral pes valgus, genu valgum, and scoliosis. Radiographs showed sphenoid bone asymmetry and deformity of the left side of the atlas.

Foley et al. (2009) described a 7-year-old boy with global developmental delay, slightly broad halluces and terminal phalanges but normal thumbs, and facial dysmorphism reminiscent of RSTS, especially while smiling, in whom they identified a de novo deletion in the EP300 gene (602700.0007). Dysmorphic features included microcephaly, slightly prominent columella, long eyelashes with rather full arched eyebrows, overlapping toes, and evidence of hirsutism on his back with a hair tuft on the left paravertebral region.

Bartsch et al. (2010) reported a 3-year-old boy with RSTS2. He had severe microcephaly, retrognathia, broad thumbs and great toes, and delayed psychomotor development with marked speech delay. He also had posterior helical pits, but normal palpebral fissures, nose, and mouth. Genetic analysis identified an apparently de novo heterozygous mutation in the EP300 gene (638delG; 602700.0008). Bartsch et al. (2010) proposed that RSTS individuals with EP300 mutations have a slightly different phenotype than those with CREBBP mutations, including less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure.

Woods et al. (2014) reported a 5-year-old Caucasian male with a phenotype suggesting Cornelia de Lange syndrome (CDLS; 122470) in whom no mutations were found in CDLS-related genes. The boy presented with intrauterine growth restriction, failure to thrive, microcephaly, cryptorchidism, hirsutism, short stature, and intellectual disability. He also had severe progressive scoliosis and chest deformity. He did not have the cardinal features of RSTS such as the typical facial gestalt or broad thumbs or toes. Exome sequencing after the child's death from bronchopneumonia identified a novel mutation in the EP300 gene (602700.0009). Autopsy showed intestinal malrotation, lung lobulation, and genitourinary anomalies. Woods et al. (2014) noted that this was the fourth RSTS case with a mutation in EP300 associated with preeclampsia and premature birth.

Hamilton et al. (2016) described 9 unrelated patients, aged 3 to 19 years, with RSTS2. Two of the pregnancies were complicated by preeclampsia. All 9 patients had mild or moderate intellectual impairment, and 8 had delays in gross motor development. Eight patients had behavioral or social difficulties, and 3 had a diagnosis of autism spectrum disorder. Typical dysmorphic features were variably present. Additional features included scoliosis in 2, syndactyly in 3, feeding/swallowing issues beyond the neonatal period in 3, and hypermobility or dislocation of the elbow in 2. Three patients had overlapping features with Floating-Harbor syndrome (136140), including thin upper vermilion, long nose, and low-hanging columella in 2 and delayed bone age in 2.

Molecular Genetics

In 3 of 92 patients with a clinical diagnosis of RSTS, Roelfsema et al. (2005) identified 3 different mutations in the EP300 gene (602700.0003-602700.0005), and stated that these were the first mutations found in EP300 as the basis of a congenital disorder. EP300 and CREBBP (600140) both function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways, and both are potent histone acetyltransferases. These findings suggested that the disorder is caused by aberrant chromatin regulation.

In 1 (2.6%) of 38 patients with RSTS who did not have mutations in the CREBBP gene, Zimmermann et al. (2007) identified a mutation in the EP300 gene (602700.0006) predicted to result in mild protein truncation. The patient had a very mild form of the disorder. Zimmermann et al. (2007) concluded that mutations in the EP300 gene play only a minor role in the etiology of RSTS.

In a 7-year-old boy with global developmental delay and a mild skeletal phenotype but facial dysmorphism reminiscent of RSTS, especially while smiling, Foley et al. (2009) identified a de novo deletion in the EP300 gene (602700.0007).

Using high resolution array comparative genomic hybridization (array CGH) targeting exons, Tsai et al. (2011) identified a de novo 5-kb deletion on chromosome 22q13.32 encompassing exons 24 to 27 of the EP300 gene in a girl referred for mild developmental delay and mild dysmorphic features. The diagnosis was consistent with RSTS2. She had microcephaly, short stature, and behavioral problems, but notably did not have abnormalities of the thumb or great toe. Her mother had preeclampsia during the pregnancy, and the patient was born prematurely at age 28 weeks' gestation.

Hamilton et al. (2016) reported heterozygous de novo mutations at highly conserved residues in the EP300 gene in 9 unrelated patients from the UK or Ireland with RSTS2. Six mutations were truncating mutations and 3 were missense (see, e.g., 602700.0010 and 602700.0011) mutations. Hamilton et al. (2016) confirmed all 9 mutations by Sanger sequencing.