Antibody deficiency in Rubinstein‐Taybi syndrome

The developmental disorder Rubinstein‐Taybi syndrome (RTS) is frequently complicated by recurrent respiratory infections. In many cases this is likely to be the result of microaspiration or gastro‐oesophageal reflux but, in a proportion, underlying antibody deficiency is a potentially modifiable susceptibility factor for infection. Relatively subtle, specific defects of pneumococcal antibody production have previously been described in the context of RTS. Here, we report a rare association between the syndrome and an overt, major primary antibody deficiency disorder (common variable immune deficiency) which was successfully managed with immunoglobulin replacement therapy. Early recognition and investigation for antibody deficiency associated with RTS allied to effective and optimized treatment are essential to minimize morbidity and mortality and improve quality and duration of life.     

Rubinstein–Taybi syndrome with thymic hypoplasia

We report the autopsy findings in a 20-month-old boy with Rubinstein–Taybi syndrome and DiGeorge sequence. No Visible thymus was demonstrated at the time of autopsy. With careful microscopic examination, a few pieces of thymic tissues found near the thyroid gland showed remarkable depletion of both thymocytes and cortical epithelial cells. Immunohistological stanining with T-cell. Surface antigens resulted in adefinite positive reaction. Repeated respiratory infections present in this patient may, in part, be attributable to thymic hypoplasia. Other major anomalies included broad thumbs and great toes, microphthalmia, arrhinencephaly, patent ductus arteriosus, stenosis of the uretero-vesicular junction, bilateral cryptorchidism, and minor facial anomalies. © 1993 Wiley-Liss, Inc.     

Rubinstein‐Taybi syndrome in Chinese population with four novel mutations

Rubinstein‐Taybi syndrome (RSTS, OMIM*180849) is a rare autosomal dominant disorder, characterized by distinctive facial features, short stature, broad and often angulated thumbs and halluces, with occasional congenital anomalies. Characteristic facial dysmorphic features include downslanting palpebral fissures, low hanging columella. RSTS is caused by pathogenic variants in two ubiquitously expressed and highly homologous genes, CREBBP (OMIM*600140) and EP300 (OMIM*600140). Clinical features were well reported especially in Caucasian ethnicity. We would like to report the clinical phenotype of RSTS in our Chinese population and highlight four novel mutations in CREBBP gene.     

Benign and malignant tumors in Rubinstein–Taybi syndrome

Rubinstein–Taybi syndrome (RSTS) is a multiple congenital anomalies syndrome associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of specific benign and possibly also malignant tumors. We identified all known individuals diagnosed with RSTS in the Netherlands until 2015 (n = 87) and studied the incidence and character of neoplastic tumors in relation to their CREBBP/EP300 alterations. The population–based Dutch RSTS data are compared to similar data of the Dutch general population and to an overview of case reports and series of all RSTS individuals with tumors reported in the literature to date. Using the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA Foundation), 35 benign and malignant tumors were observed in 26/87 individuals. Meningiomas and pilomatricomas were the most frequent benign tumors and their incidence was significantly elevated in comparison to the general Dutch population. Five malignant tumors were observed in four persons with RSTS (medulloblastoma; diffuse large‐cell B‐cell lymphoma; breast cancer; non‐small cell lung carcinoma; colon carcinoma). No clear genotype–phenotype correlation became evident. The Dutch population‐based data and reported case studies underscore the increased incidence of meningiomas and pilomatricomas in individuals with RSTS. There is no supporting evidence for an increased risk for malignant tumors in individuals with RSTS, however, due to the small numbers this risk may not be fully dismissed.     

Possible case of Rubinstein‐Taybi syndrome in a prehistoric skeleton from west‐central Illinois

I describe an adult female skeleton (#Yo3‐96) from the Yokem Mound skeletal series that had microcephaly; mild micrognathia; a broad nasal bridge; orbital hypertelorism; hypoplasia of the first metacarpals; pes planus; anomalies of the cervical spine, ribs, and sternum; and delayed epiphyseal remodeling of the radii and tibiae. Because the Yokem series has been subject to extensive measurement in previous studies, Yo3‐96 can be characterized metrically and compared with others from her population. A differential diagnosis is made by comparing the available skeletal evidence with the known syndromes characterized by radial ray dysplasia. It is suggested that Yo3‐96 represents the earliest known case of Rubinstein‐Taybi syndrome, a mental retardation syndrome that has been described in individuals from several modern populations. Am. J. Med. Genet. 91:56–61, 2000. © 2000 Wiley‐Liss, Inc.     

Psychopathology,GABA, and the Rubinstein‐Taybi syndrome: A review and case study

An adult female with congenital Rubinstein‐Taybi syndrome (RTS) and severe mental retardation is described, who presented with symptoms of severe over‐activity, short attention span, mood lability, and aggressive outbursts in a cyclical pattern, suggestive of recurrent manic‐like episodes. These symptoms improved significantly with divalproex (Depakote) monotherapy. Review of the existing studies showed that 10–76% of persons with RTS may be identified with similar behavioral symptoms. We postulate other persons with RTS may respond to divalproex, and there may be some relationship between the chromosome 16p13.3 deletion and γ‐aminobutyric acid (GABA) receptor or neurotransmitter abnormalities. Recent molecular genetic studies suggest a linkage of this region to bipolar mood disorder and autism, both of which were diagnosed in this patient. Further prospective study is needed of RTS persons regarding behavioral problems, comorbid psychiatric diagnoses, and treatment responses, correlated with genetic abnormalities. © 2002 Wiley‐Liss, Inc.     

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

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.     

Transient hypoglycemia with hyperinsulinemia in a newborn infant with Rubinstein–Taybi syndrome

A newborn boy with Rubinstein–Taybi syndrome who had profound neonatal hypoglycemia is presented. The infant was a discordant fraternal twin with intrauterine growth retardation. The hypoglycemia was due to transient hyperinsulinemia, a condition often seen in small-for-gestational-age infants. Neonatal hypoglycemia may be common in infants with Rubinstein–Taybi syndrome, especially if they also have intrauterine growth retardation.     

Holt-Oram syndrome associated with the hypoplastic left heart syndrome

We present the first case of Holt-Oram syndrome associated with the lethal congenital heart defect of hypoplastic left heart syndrome. The possible pathophysiological link is explored and the need for careful genetic and cardiologic evaluation in these patients is reiterated.     

Rubinstein‐Taybi syndrome caused by a de novo reciprocal translocation t(2;16)(q36.3;p13.3)

Rubinstein‐Taybi syndrome (RTS) is a multiple congenital anomalies and mental retardation syndrome characterized by facial abnormalities, broad thumbs, and broad big toes. We have shown previously that disruption of the human CREB‐binding protein (CBP) gene, either by gross chromosomal rearrangements or by point mutations, leads to RTS. Translocations and inversions involving chromosome band 16p13.3 form the minority of CBP mutations, whereas microdeletions occur more frequently (∼10%). Breakpoints of six translocations and inversions in RTS patients described thus far were found clustered in a 13‐kb intronic region at the 5′ end of the CBP gene and could theoretically only result in proteins containing the extreme N‐terminal region of CBP. In contrast, in one patient with a translocation t(2;16)(q36.3;p13.3) we show by using fiber FISH and Southern blot analysis that the chromosome 16 breakpoint lies about 100 kb downstream of this breakpoint cluster. In this patient, Western blot analysis of extracts prepared from lymphoblasts showed both a normal and an abnormal shorter protein lacking the C‐terminal domain, indicating expression of both the normal and the mutant allele. The results suggest that the loss of C‐terminal domains of CBP is sufficient to cause RTS. Furthermore, these data indicate the potential utility of Western blot analysis as an inexpensive and fast approach for screening RTS mutations. Am. J. Med. Genet. 92:47–52, 2000. © 2000 Wiley‐Liss, Inc.