Paola Francesca Ajmone

Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management

BackgroundRubinstein-Taybi syndrome (RSTS) is an extremely rare autosomal dominant genetic disease, with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical facial features, microcephaly, broad thumbs and first toes, intellectual disability, and postnatal growth retardation. However, no standard diagnostic criteria are available for RSTS. In this review, we summarized the clinical features and genetic basis of RSTS and highlighted areas for future studies on an appropriate diagnostic protocol and follow-up care for RSTS.DiscussionRSTS is primarily characterized by delayed growth in height and weight, microcephaly, dysmorphic facial features, and broad thumbs and big toe. Over 90% RSTS individuals with disabilities survive to adulthood, but healthcare for these patients is particularly complex, time-consuming, and costly. In addition, no standard diagnostic criteria and follow-up care guidelines are available for RSTS. It has been shown that mutations in the genes encoding the cyclic-AMP-regulated enhancer binding protein (CREBBP) and the E1A-binding protein p300 (EP300) contributed to the development of RSTS. Therefore, genetic tests are useful for the diagnosis of RSTS, although most RSTS cases are currently diagnosed based on clinical features.SummaryThe clinical features of RSTS have been extensively studied, which significantly contributes to the diagnosis of this extremely rare syndrome. However, the pathogenesis and genotype-phenotype associations of RSTS are largely unknown. Therefore, multicenter studies and international cooperation are highlighted for better understanding of this disease, establishing standard diagnostic criteria, and providing professional management and follow-up care of RSTS.

Communication, cognitive development and behavior in children with Cornelia de Lange Syndrome (CdLS): Preliminary results

In this study, we present preliminary data on cognitive, behavioral and communication domains of individuals with Cornelia de Lange Syndrome (CdLS), collected through a specific protocol combining direct and indirect tools. Seventeen subjects with CdLS were assessed, 2.5‐ to 13.4‐year‐old. Cognitive level of the subjects differed from what previously described in literature, showing more patients with normal or borderline cognitive abilities. We found a relation between severe autistic behavior and comprehension impairments: all children with high CARS score have severe receptive language disability. A correlation was also found between CARS score and ID: high CARS score occurred only in patients with profound levels of ID. Results of this study support the need for a specific assessment protocol tailored for the characteristics of subjects with multiple disabilities, to be able to identify their strengths avoiding the avalanche effect of weaknesses. Most tests on neuropsychological functions have been developed and standardized for typically developing children, and require the integrity of other functions aside the one that is evaluated, determining an underestimation of the level of functioning. This study could be a starting point to develop new models applicable to other genetic syndromes and complex situations; new and wider studies are needed in order to allow a more complete and accurate assessment, thereby ensuring more efficient and family‐centered treatment plans.

A new prognostic index of severity of intellectual disabilities in Cornelia de Lange syndrome

Cornelia de Lange syndrome is a well‐known multiple congenital anomalies/intellectual disability syndrome with genetic heterogeneity and wide clinical variability, regarding the severity of both the intellectual disabilities and the physical features, not completely explained by the genotype‐phenotype correlations known to date. The aim of the study was the identification of prognostic features, ascertainable precociously in the patients life, of a better intellectual outcome and the development of a new prognostic index of severity of intellectual disability in CdLS patients. In 66 italian CdLS patients aged 8 years or more, we evaluated the association of the degree of intellectual disability with various clinical parameters ascertainable before 6 months of life and with the molecular data by the application of cumulative regression logistic model. Based on these results and on the previously known genotype‐phenotype correlations, we selected seven parameters to be used in a multivariate cumulative regression logistic model to develop a prognostic index of severity of intellectual disability. The probability of a mild ID increases with the reducing final score less than two, the probability of a severe ID increases with the increasing final score more than three. This prognostic index allows to define, precociously in the life of a baby, the probability of a better or worse intellectual outcome in CdLS patients.

Adolescents and adults affected by Cornelia de Lange syndrome: A report of 73 Italian patients.

Cornelia de Lange syndrome (CdLS) is a rare genetic condition related to mutation of various cohesion complex related genes. Its natural history is quite well characterized as regard pediatric age. Relatively little information is available regarding the evolution of the disease in young‐adult age. In medical literature, only one specific study has been published on this topic. We report on our experience on 73 Italian CdLS patients (40 males and 33 females) with and age range from 15 to 49 years. Our results confirm the previous study indicating that gastroesophageal reflux disease (GERD) is the main medical problem of these patients in childhood and young‐adult age. Other medical features that should be considered in the medical follow‐up are tendency to overweight/frank obesity, constipation, discrepancy of limbs’ length, epilepsy, hearing, and visual problems. Behavioral problems are particularly frequent as well. For this reason, every source of hidden pain should be actively searched for in evaluating a patient showing such a disorder. Finally, recommendations for medical follow‐up in adult age are discussed.

A new report of Cornelia de Lange syndrome associated with split hand and feet

We report on a boy with clinical and molecular diagnosis of Cornelia de Lange syndrome (CdLS). Besides the CdLS typical features, he shows split hand and split feet. To the best of our knowledge, only one other patient with similar finding has been reported in CdLS patients.

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.

Sleep disorders in Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. Sleep disturbances have been frequently reported in CdLS, but these have not been completely characterized, and prevalence data are conflicting. The aim of this paper is to characterize and determine the prevalence of sleep disorders in CdLS patients by means of a validated questionnaire. From November 2012 to November 2013, we asked 46 consecutive parents/caregivers of CdLS patients aged more than 3 years old to fill out the sleep disturbances scale for children (SDSC). The subjects were also characterized by the presence of epilepsy, intellectual disability (ID), behavioral problems, CdLS severity score, gastroesophageal reflux disease (GERD), and genetic test results. An abnormal total sleep score was found in 7 patients (15.2%), 26 (56.5%) showed a borderline total score, and 18 (39.1%) had an abnormal score for at least one SDSC factor. In our study sleep disorders were found to be positively associated to presence of epilepsy, GERD, ID, and behavioral disturbances. No correlation was evident with specific mutations of the different genes, BMI, and severity score. Our results confirm that sleep disorders represent a common problem in CdLS, with higher incidence than in the normal population. In these patients sleep disorders seem to be more prevalent in comorbid settings, representing a clinical indicator for different medical and neuropsychiatric disorders. Better knowledge and characterization of typology of sleep disorders in CdLS patients could permit a more specific therapeutic approach.

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.Cornelia de Lange syndrome is a genetic disorder affecting multiple organ systems that exhibits great phenotypic heterogeneity. This Consensus Statement summarizes recommendations for the diagnosis and management of patients with Cornelia de Lange syndrome.

Microdeletion 2q23.3q24.1: Exploring genotype-phenotype correlations

We report a case of a 13‐year‐old girl with a 5.4Mb de novo deletion, encompassing bands 2q23.3q24.1, identified by array‐comparative genomic hybridization. She presented with minor facial and digital anomalies, mild developmental delay during infancy, and behavioral disorders. Few of the reported cases overlap this deletion and all only partially. We tried to compare the clinical features of the patient with the other cases, even though not all of them were molecularly characterized in detail. Considering the neuropsychiatric involvement of the proband and the clinical descriptions of other similar cases, we attempted to identify the genes more probably involved in neurological development and function in the deleted region, particularly GALNT13, KCNJ3 and NR4A2, which are expressed in neuronal cells.

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

PurposeMowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.