Rubinstein-Taybi syndrome

Was ist Rubinstein-Taybi syndrome?

Rubinstein-Taybi syndrome is a very rare genetic condition and occurs in anywhere between 1 in 100-300,000 live births. It occurs in males and females equally.

Health conditions associated with Rubinstein-Taybi syndrome vary considerably between individuals with the syndrome and also vary in their severity between individuals. These health conditions usually include broad thumbs and first toes, developmental delay and intellectual disability, characteristic facial features, and possible cardiac and respiratory problems.

Was Genveränderungen verursachen Rubinstein-Taybi syndrome?

Rubinstein-Taybi syndrome occurs, in 50-60% of cases, due to pathogenic variants in the CREBBP gene. In the remainder of cases, mutations in EP300 are believed to be the cause. The syndrome occurs randomly and is not generally inherited.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

Was sind die wichtigsten symptome von Rubinstein-Taybi syndrome?

The main symptoms of Rubinstein-Taybi syndrome vary considerably between individuals and may also vary in the extent of their severity.

Common symptoms include broad thumbs and 1st toes and downward slanted eyes, widely-spaced eyes, high arched eyebrows, droopy eyelids, and long eyelashes. Frequent eye infections are another common symptom of the syndrome.

Mild to severe intellectual disability and developmental delay is also characteristic of Rubinstein-Taybi syndrome. There are associations between the syndrome and a higher risk of a diagnosis for autism, ADHD, and other impulse associated disorders.

Some possible but not necessarily exclusive symptoms include short stature, small head and jaw, a high arched palate, excessive hairiness, as well as potential cardiac and respiratory problems.

Wie wird jemand getestet? Rubinstein-Taybi syndrome?

Die ersten Tests für Rubinstein-Taybi syndrome kann mit einem Gesichtsanalyse-Screening beginnen, durch die FDNA Telehealth Telegenetik-Plattform, die die Schlüsselmarker der syndrom und skizzieren Sie die Notwendigkeit weiterer Tests. Es folgt ein Beratungsgespräch mit einem genetischen Berater und dann einem Genetiker. 

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medizinische Informationen zu Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome features broad thumbs and first toes, distinctive facial features (downslanted palpebral fissures, high palate, beaked nose, grimacing smile, and talon cusps), short stature, and intellectual disability. Rubinstein-Taybi syndrome 1 is caused by heterozygous mutations in the CREBBP gene on chromosome 16p13.3.

There are several syndromes where broad thumbs are a feature. In order to make a diagnosis of Rubinstein-Taybi syndrome the characteristic craniofacial abnormalities should be present. These are microcephaly (not all are - Wieczorek et al., 2009), antimongoloid eye slant, hypertelorism, long eyelashes, mild ptosis, posteriorly rotated ears and a convex nose with the columella protruding below the alae nasi on lateral view. The thumbs and halluces are broad, or occasionally bifid, with medial deviation. The tips of the other fingers may be spatulate. Dislocation of the patellar may be a common feature (Stevens 1997). The facial features become more marked with age. Stevens and Bhakta (1995) carried out a questionnaire survey that indicated that around 30% of cases have a cardiac anomaly. The most common lesions were a VSD, ASD and PDA. Lin et al., (1999) found similar features. Shashi et al., (1995) reported a case with a vascular ring causing tracheoesophageal compression. Schepis et al., (2001) reported a case with an epidermal nevus of the trunk and leg. Miller and Rubinstein (1995) reviewed 36 cases where tumours have been reported. Neural and developmental tumours were common. Ihara et al., (1999) reported a case with a neuroblastoma and premature thelarche. Kurosawa et al., (2002) reported three further females with premature thelarche and review other cases in the literature. Some cases may have keloids (Hendrix and Greer 1996). Central nervous system anomalies including Dandy-Walker malformations have been reported (Mazzone et al., 1989 and Agarwal et al., 2002). A tethered spinal cord was found in 8 patients (Tanaka et al., 2006). Villella et al., (2000) reported an apparent case with immunodeficiency, however no photographs were given. A number of ocular features have been reported, including congenital glaucoma, cataracts, corneal abnormalities, colobomas, lacrimal duct obstruction and retinal abnormalities with an abnormal VEP (van Genderen et al., 2000). Stature is occasionally normal, and 2 patients have had camptodactyly of the 3rd (and 4th) fingers - Wieczorek et al., 2009).
Variable expression - some cases (with mutations) having mild facial features and some with only broad thumbs and big toes were reported by Bartsch et al., (2010).
Hennekam et al., (1990) noted that sleep problems are seen in about 10% of cases, possibly due to sleep apnoea. Collapse of the laryngeal wall may be a cause. This should be noted if anaesthesia is contemplated. In addition cardiac arrhythmia secondary to neuromuscular blocking agents such as succinylcholine has been reported (Stirt, 1981).
Wiley et al., (2003) suggest medical guidelines for management.
Most cases are sporadic. Several sets of concordant monozygotic twins have been described (Baraitser et al., 1983; Robinson et al., 1993).
Takeuchi (1966) reported less convincingly affected siblings. Hennekam et al., (1989) reported an affected mother and son and Marion et al., (1993) a mother and daughter, suggesting dominant inheritance.
Guion-Almeida and Richieri-Costa (1992) reported a convincing case with unusual association of an iris coloboma, a megacolon and agenesis of the corpus callosum. Cambiaghi et al., (1994) reported a case with multiple pilomatricomas (benign epithelial neoplasms with hair cell differentiation). Skousen et al., (1996) reported a case with a medulloblastoma however no clinical photographs were published. The oro-dental features were reviewed by Bloch-Zupan et al., (2007).
A girl (Marzuillo et al., 2013) with a CREBBP mutation (no facial pictures shown) had in addition growth hormone deficiency, Arnold Chiari malformation and pituitary hypoplasia.
Prenatal diagnosis was achieved by Bedeschi et al., (2014), by finding the characteristic facial and thumb anomalies. There were also posterior fossa abnormalities.(cerebellar vermis hypoplasia). Final diagnosis at 33 weeks. Keloids occur in 24% of cases (van der Kar et al., 2014)
Breuning et al., (1993) demonstrated a deletion on 16p13 using FISH. This deletion was submicroscopic and could be found in 25% of cases. Wallerstein et al., (1997) found submicroscopic deletions in 7 out of 64 patients with the syndrome (11%). Bartsch et al., (1999) found 4 deletions out of 45 patients (8.9%). Two patients had accessory spleen and one patient a hypoplastic left heart, abnormal pulmonary lobulation and renal agenesis. Blough et al., (2000) used cosmid probes spanning the CBP gene in a panel of 66 cases and found deletions in 5 (9%). Petrij et al., (2000) used five cosmids spanning the CBP gene and found 10% had microdeletions. Hennekam et al., (1993) could find no evidence of uniparental disomy and no clinical differences between patients with or without the demonstrable microdeletion. Petrij et al., (1995) demonstrated point mutations in the CBP gene. This codes for a protein that binds to the phosphorylated form of the CREB transcription factor. This increases the expression of genes containing cyclic AMP-responsive elements. Coupry et al., (2002) studied 63 patients and found three micro-deletions in the CBP gene by FISH analysis, three gross rearrangements by Southern blot, one small intragenic deletion by RT-PCR and one truncated RNA by Northern blot analysis. 22 point mutations were also identified. Bartsch et al., (2002) reported ten further mutations including a mildly affected 15-year-old girl with low normal intelligence and a missense mutation. Coupry et al., (2004) reported the detection of deletions in 4 out of 13 patients, using RT-PCR, that were missed on FISH. In a series of 92 patients screened bu Roelfsma et al., (2005) for CBP mutations, 36 were found.
Because of the homology of CBP with EP300 on chromosome 22 (22q13), Roelfsma et al., (2005) looked for mutations there, and found 3. Bartsch et al., (2005) found that 56% of patients with unequivocal RTS had mutations, and a 25% figure in those with an incomplete form. They concluded that 30% of clinical RTS is caused by other genes. Those with the EP300 mutation have milder skeletal findings in the hands and feet (Bartholdi et al., 2007). Bartsch et al., (2010) suggest that the facial dysmorphism is also different in that the palpebral fissures are horizontal and posterior helicalare present. A non-classical (IQ75) patient reported by Zimmermann et al., (2007) had a 1-bp deletion of EP300. A milder skeletal phenotype in those with EP300 mutations was again emphasised by Foley et al., (2009).
Hennekam (2006) provides an excellent review. Somatic and germ-line mosaicism have been reported (Chiang et al., 2009). Note the occurrence in 2 first cousins who carry different mutations (Balci et al., 2010).
Eleven patients with heterozygous mutations in the CREBBP gene and two with heterozygous mutations in the EP300 but without Rubinstein-Taybi syndrome characteristics were reported by Menke et. al. (2018). Clinical characteristics included flat or square face, telecanthus, short and upslanting palpebral fissures, squint, depressed nasal bridge, upper lip thin vermillion, intellectual disability, and feeding problems.

* This information is courtesy of the L M D.
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