Rubinstein–Taybi syndrome: New neuroradiological and neuropsychiatric insights from a multidisciplinary approach

Abstract

Rubinstein-Taybi syndrome is a rare, autosomal dominant, plurimalformative disorder that is clinically characterized by intellectual disability and a wide spectrum of congenital anomalies; facial dysmorphisms are typical, and broad thumbs and great toes are particularly distinctive. Its genetic basis is only partially known, with a detection rate of approximately 65-70%; specifically, microdeletions or mutations in the CREBBP or EP300 genes can be found. Much is known about its clinical features and health-care protocols, but some areas of clinical knowledge are currently unsolved. In particular, few efforts have been made until now to understand the variability in the neuropsychological and neurobehavioral profile and to deepen knowledge of the neuroradiological malformative pattern. Consequently, little is known about the possible genotype-phenotype correlations of these issues. Here, we report clinical and genetic data from a cohort of 23 RSTS Italian patients. The most common features in brain magnetic resonance imaging (MRI) were dysmorphic aspects of the corpus callosum (73.6%) with or without minor dysmorphisms of cerebellar vermis, periventricular posterior white matter hyperintensity, and other less common anomalies. The most interesting feature on the whole spine MRI scans was the tendency for a low-lying conus medullaris without terminal filum thickening. These data will help to improve neuropsychiatric and neuroradiological knowledge and highlight specific genotype-phenotype correlations.

Expanding the phenotype of Wiedemann‐Steiner syndrome: Craniovertebral junction anomalies

“…Furthermore, protein–protein interaction networks (https://string-db.org/) show known and predicted interactions with other proteins having a role in histone‐mediated chromatin remodeling. CREBBP, an interactor of the KMT2A transactivator domain, supports the role of some of these proteins in CVJ anomalies: de novo LoF/deletion variants in the CREBBP gene are responsible for Rubinstein‐Taybi syndrome 1 (RSTS1, OMIM # 180849), a severe multisystemic disorder in which Chiari malformation type I is common (Ajmone et al, 2018; Lee et al, 2015) and a high risk of cervical vertebral anomalies has been reported, including vertebral fusion and abnormalities of the odontoid process (Milani et al, 2015; Yamamoto et al, 2005). Similar findings in a few cases of Kabuki syndrome (OMIM # 147920 and # 300867; Ciprero et al, 2005)—and in particular in one case associated with a LoF variant of KDM6A (Cheon & Ko, 2015)—further point to alterations in histone acetylation and methylation as causative of Chiari type I.…”

“…CREBBP, an interactor of the KMT2A transactivator domain, supports the role of some of these proteins in CVJ anomalies: de novo LoF/deletion variants in the CREBBP gene are responsible for Rubinstein-Taybi syndrome 1 (RSTS1, OMIM # 180849), a severe multisystemic disorder in which Chiari malformation type I is common (Ajmone et al, 2018;Lee et al, 2015) and a high risk of cervical vertebral anomalies has been reported, including vertebral fusion and abnormalities of the odontoid process (Milani et al, 2015;Yamamoto et al, 2005). Similar findings in a few cases of Kabuki syndrome (OMIM # 147920 and # 300867;Ciprero et al, 2005) other cervical defects (e.g., vertebral fusion), they may lead to severe neurological deterioration (Connor et al, 2001).…”

Olfactory Malformations in Mendelian Disorders of the Epigenetic Machinery

“…Therefore, when genetic disorders disrupt epigenetic machinery molecules, brain malformations are a near-constant. This seems especially true for median structures of the brain, such as the corpus callosum and the cerebellar vermis as reported by different studies (Schaefer et al, 1997;Schrier et al, 2012;Willemsen et al, 2012;Maya et al, 2014;Ajmone et al, 2018). As more and more studies on the neurological aspects of the MDEM emerge, reports on other brain malformations are revealed.…”

“…As more and more studies on the neurological aspects of the MDEM emerge, reports on other brain malformations are revealed. Searching the literature for OB hypoplasia/aplasia in these conditions unveiled a large number of studies involving CHARGE syndrome (Lin et al, 1990;Harvey et al, 1991;Pinto et al, 2005), but only a couple of human reports on RSTS and KLFS (Ajmone et al, 2018;Ciaccio et al, 2019).…”

Fetal phenotype of Rubinstein‐Taybi syndrome caused by CREBBP mutations

“…However, recently, Ajmone et al described neuroradiological insights in 23 RSTS Italian patients and reported minor dysmorphic aspects of the cerebellar vermis in 58% and olfactory bulbs hypoplasia or aplasia in 32% of cases as was observed by us in case 2. 16 Moreover, abnormalities of the gallbladder were present in 22% of cases and were detected by ultrasonography. This feature has, to the best of our knowledge, not been described before in RSTS children and may therefore represent a prenatal hallmark of the syndrome.…”