Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients.

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients' neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.

Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods.

Intestinal malrotation in Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome which may include malformations of the central nervous system, heart, genitourinary tract, and other organs. However, intestinal malrotation has not been previously known to be associated with RSTS. This report documents six persons with RSTS who also had malrotation of the intestine requiring surgical repair. This suggests a possible increased frequency of malrotation in RSTS. Diagnostic studies for malrotation should be considered if recurrent vomiting, abdominal pain, and other symptoms of possible malrotation are present.

Ultrasound 2-D and 3-D diagnosis of Rubinstein-Taybi syndrome in a 21-week-old fetus.

Rubinstein-Taybi syndrome is a rare genetic multisystem disorder with an estimated prevalence between 1 per 100,000-125,000 live births. Diagnosis is usually clinical and subsequent to birth. In fact, the rarity of the syndrome and the presence of aspecific morphologic anomalies make prenatal diagnosis challenging. The aim of our work is to analyze ultrasonographic findings, detectable with a combination of 2D and 3D techniques, which may increase the sensitivity of in utero diagnosis of this condition. We report a case of a sonographic prenatal diagnosis of broad and angulated thumbs and halluces and of an abnormal ductus venosus at 21 weeks of gestational age. These findings allowed us to suspect Rubinstein-Taybi syndrome. An accurate ultrasonographic examination may allow a prenatal diagnosis of those syndromes which are usually diagnosed after birth.

The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration.

CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBPFl/Fl, mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system.Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses.In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients' quality of life.

Rubinstein-Taybi syndrome and mixed bilateral hypoacousia case report.

OBJECTIVE: To describe a case of Rubinstein-Taybi syndrome (RTS) in association with mixed bilateral hypoacousia. PATIENT: A 10-year-old boy presented at a private otology practice center in Bogotá, Colombia, with signs and symptoms of RTS. In addition, the patient presented with mixed bilateral conductive hypoacousia, predominantly in the left ear with a 40- to 50-dB conductive component, caused by middle ear malformations and fixation of the ossicular chain and stapes footplate. INTERVENTION: The patient underwent a left exploratory tympanotomy and then a stapedotomy. MAIN OUTCOME MEASURES: Computed tomography, genetic evaluation, and audiologic testing. RESULTS: Postoperative recovery was normal. There was closure of the conductive gap (< or =10 dB) with improvement of subjective hearing. CONCLUSION: We presented a case of a patient with RTS and bilateral mixed hypoacousia who underwent a stapedotomy with a final improvement in his hearing performance. We consider it important to report and describe the simultaneous presence of these pathologic findings and to be able to analyzeif these otologic findings are coincidental or truly associated with RTS.

Electroclinical phenotype in Rubinstein-Taybi syndrome.

OBJECTIVE: Rubinstein-Taybi syndrome (RSTS) is a rare congenital disorder (1:125.000) characterized by growth retardation, psychomotor developmental delay, microcephaly and dysmorphic features. In 25% of patients seizures have been described, and in about 66% a wide range of EEG abnormalities, but studies on neurological features are scant and dated. The aim of this study is to describe the electroclinical phenotype of twenty-three patients with RSTS, and to try to correlate electroclinical features with neuroradiological, cognitive and genetic features. PATIENTS AND METHODS: Electroclinical features of twenty-three patients with RSTS (age between18months and 20years) were analyzed. Sleep and awake EEG was performed in twenty-one patients, and brain MRI in nineteen patients. All subjects received cognitive evaluation. RESULTS: EEG abnormalities were observed in 76% (16/21) of patients. A peculiar pattern prevalent in sleep, characterized by slow monomorphic activity on posterior regions was also observed in 33% (7/21) of patients. Almost no patient presented seizures. Eighty-four percentage of patients had brain MRI abnormalities, involving corpus callosum and/or posterior periventricular white matter. Average General Quotient (GQ) was 52, while average IQ was 55, corresponding to mild Intellectual Disability. The homogeneous electroclinical pattern was observed mainly in patients with more severe neuroradiologic findings and moderate Intellectual Disability/Developmental Disability (ID/DD). No genotype-phenotype correlations were found. CONCLUSION: The specific electroclinical and neuroradiological features described may be part of a characteristic RSTS phenotype. Wider and longitudinal studies are needed to verify its significance and impact on diagnosis, prognosis and clinical management of RSTS patients.

Patellar dislocation in Rubenstein-Taybi syndrome.

This report describes 11 patients with Rubinstein-Taybi syndrome (RTS) and patellar dislocation. The age at diagnosis of patellar dislocation ranged from birth to 16 years. Ten patients had chronic dislocations and 8 of 11 had bilateral patellar dislocations. Eight patients required surgical stabilization of the patella; most achieved a good outcome with surgical repair. All families reported that the patellar dislocations impaired developmental skills which improved after surgery. Seven of the 11 patients were described as having other joint abnormalities including congenital dislocations and laxity of the joints. Patients with RTS should undergo regular thorough joint examinations, including the knees, because abnormalities may result in delay of attainment of motor skills.

Bilateral congenital corneal keloids and anterior segment mesenchymal dysgenesis in a case of Rubinstein-Taybi syndrome.

PURPOSE: To report the unusual association of bilateral corneal keloids and anterior segment mesenchymal dysgenesis in a child with Rubinstein-Taybi syndrome. METHODS: Case report of a 2-year-old boy. RESULTS: Excision of the epicorneal mass in the right eye was followed by recurrence of the lesion. Multiple penetrating keratoplasties were unsuccessful in reconstructing the anterior segment because of recurrent corneal epithelial breakdown, suggesting limbal stem cell insufficiency. Histopathology and electron microscopy of the excised mass lesion showed features typical of a corneal keloid: thickened keratinized epithelium, absent Bowman's layer, and fibrovascular hyperplasia, with haphazard orientation of the collagen lamellae. Ultrasound biomicroscopy and intraoperative findings suggested a diagnosis of Peter anomaly, but genetic analysis did not show a PAX6 mutation. CONCLUSION: The findings in our patient add to the spectrum of ocular changes described in Rubinstein-Taybi syndrome and confirm earlier reports of poor ocular prognosis in corneal keloids and Rubinstein-Taybi syndrome.

[Taybi-Rubinstein syndrome: the value of the x-ray picture]. / Taybi-Rubinstein-Syndrome: Der Stellenwert des Röntgenbildes.

28 cases of Taybi-Rubinstein syndrome with different radiological appearances are presented along with radiological differential diagnosis. Broadening of the distal phalanx of the thumb (68%) and great toe (64%) was the most common radiological sign followed by incomplete fissures of the distal phalanges of the thumb and first toes. Radiological examination in association with clinical signs and laboratory investigations is an essential part in the diagnosis of the Taybi-Rubinstein syndrome.

Cervical spondylolisthesis and other skeletal abnormalities in Rubinstein-Taybi syndrome.

A patient with Rubinstein-Taybi syndrome complicated by tetraplegia secondary to cervical spondylolisthesis is reported. The abnormalities presenting in this condition are reviewed.

Dandy-Walker malformation in Rubinstein-Taybi syndrome: a rare association.

A female infant is described with the rare association of Dandy-Walker malformation in Rubinstein-Taybi syndrome.

Bone scan-demonstrated urinary tract abnormalities in a patient with Rubinstein-Taybi syndrome.

A 22-month-old boy had a Tc-99m-MDP bone scan. This revealed multiple urinary tract anomalies (bladder distention, ectopic and small right kidney, hypertrophied left kidney, and bilateral hydronephrosis). The defects, fortuitously appreciated by means of the bone images, led to the correct diagnosis of urinary retention and infection as the cause of the child's symptoms. The urinary tract anomalies were associated with the Rubinstein-Taybi syndrome.

Long-term results following osteotomy of the thumb delta phalanx in Rubinstein-Taybi Syndrome.

Rubinstein-Taybi Syndrome is a rare condition affecting 1:125,000 children. It is associated with short broad radially deviated thumbs, secondary to a delta proximal phalanx of the thumb. We undertook a retrospective review of seven children (13 thumbs) with Rubinstein-Taybi syndrome whose thumbs were treated using a corrective osteotomy to the delta phalanx over a 13 year period. The types of osteotomy used in the series were reverse wedge osteotomy, opening wedge osteotomy and dome shaped osteotomy. The mean preoperative radial deviation of thumbs was 68 degrees (range 45-85 degrees ). At follow up five of the 13 thumbs demonstrated some residual radial deviation. All recurrences occurred in the dome shaped osteotomy group. Our data suggest that surgery is effective in correcting the deformity, but there is a risk of incomplete correction or recurrence. Despite the recurrence the mean postoperative deformity was significantly better than preoperatively and the majority of patients families subjectively reported good function. No patient in our series has yet undergone further corrective surgery.