Rubinstein-Taybi syndrome and genetics
Rubinstein-Taybi syndrome (RSTS) is a genetic condition characterized by congenital anomalies and cognitive impairments, first described in 1963. This syndrome exhibits a dominant inheritance pattern and affects approximately 1 in 100,000 newborns, with a significantly higher recurrence rate in offspring of affected individuals. The primary genetic causes of RSTS involve mutations in the CREB binding protein (CREBBP) and EP300 genes, both critical for cellular signaling and development. These mutations can lead to various physical and neurological features, including broad thumbs and great toes, distinctive facial characteristics, and developmental delays.
Clinical diagnosis often involves family history and physical examinations, although genetic testing is available for about 55% of cases. Treatment typically includes early medical interventions, genetic counseling, and regular screenings for associated health issues, as individuals with RSTS may be at increased risk for certain malignancies. While no prevention strategies exist due to the de novo nature of most cases, early detection and comprehensive care can significantly improve outcomes for those affected by this syndrome.
Rubinstein-Taybi syndrome and genetics
ALSO KNOWN AS: Rubinstein syndrome; broad thumbs and great toes; broad thumb-hallux syndrome
DEFINITION Rubinstein-Taybi syndrome (RSTS) is a congenital anomaly and cognitive impairment syndrome with multisystem effects. It was first described as a syndrome by Jack Rubinstein and Hooshang Taybi in 1963 after examining multiple similar cases. RSTS is a dominant genetic condition displaying consistent physical and neurological findings. Some varying attributes are also reported in the literature.
Risk Factors
The occurrence of RSTS is approximately 1 in 100,000 newborns. The incidence increases to 50 percent of offspring of affected individuals. Various phenotypical penetrance is reported in families. Other than familial cases, there are no known risk factors.
Etiology and Genetics
RSTS is caused by a heterozygous germline (oocyte, spermatocyte) mutation. Approximately 55 percent of cases of RSTS are caused by mutations in one of two genes, the CREB binding protein (CREBBP) gene located on chromosome 16p13.3 and the EP300 gene located on chromosome 22q12.2. Both genes encode histone acetyltransferases (HAT), which affect cellular signaling pathways and are important in cell growth and differentiation. HAT plays an important role in activation of transcription. HAT blocks the restricted access to deoxyribonucleic acid (DNA). In translation, DNA gives ribonucleic acid (RNA) orders to produce a certain needed protein. RNA then produces the requested protein in a process called transcription. These proteins are utilized for cellular processes and development. CREBBP also plays a part in long-term memory formation, and its mutation may result in the cognitive deficits seen in individuals with RSTS. Mutations of these genes are usually point mutations, although translocations, inversions, missense mutations, mosaic microdeletions, and large deletions have been reported. Most mutations are dominant de novo events. The expected recurrence rate in future pregnancies is 0.1 percent. The genetic etiology of the remaining 45 percent of cases has not yet been determined.
Symptoms
RSTS is characterized by neurological and physical features. Neurologically, failure to achieve developmental milestones and mental retardation are common. Later, children exhibit short attention span and self-stimulatory behaviors such as rocking or spinning. Physically, broad great toes and thumbs are hallmarks of the syndrome. In addition, distinct facial features include down-slanting palpebral fissures, hypertelorism, high-arched eyebrows, prominent beaked nose with the nasal septum extending below the nares, a grimacing mouth, and hypoplastic maxilla. On dental exams, 90 percent of affected individuals exhibit talon cusps. Failure to thrive may follow feeding difficulties in infancy and gastroesophageal reflux is common.
Screening and Diagnosis
Diagnosis is by two methods. Clinically, it includes family history, and patient history and physical examination findings. In the absence of positive genetic tests the diagnosis is based on clinical and radiological findings which include dysmorphological facial features, broad thumbs and first toes, and mental and physical growth delay. Genetic testing now allows confirmation of suspicion in approximately 55 percent of cases using fluorescence in situ hybridization (FISH), DNA sequence analysis, and polymerase chain reaction (PCR) testing. Currently, no genetic tests can detect the syndrome in the remaining 45 percent of affected individuals.
Treatment and Therapy
Early diagnosis permits treatment of medical issues as well as the provision of genetic counseling including information about RSTS, recurrence risks, and prenatal diagnosis. In addition to genetic evaluation, the individual should be screened for cardiac, renal, ophthalmologic, auditory, endocrine, and orthopedic issues. Because of the high incidence of dental problems, referral and follow-up by a pediatric dentist is needed. Because of feeding difficulties, growth and nutrition counseling is beneficial. Individuals with CREBBP and EP300 gene mutations are at risk for future malignancies due to an imbalance of alleles implicated in malignancies such as hematologic, breast, ovarian, hepatic, and colorectal cancer and require close monitoring for development of these tumors.
Prevention and Outcomes
No identifiable prevention strategy is currently known to prevent the majority of cases, as they are primarily due to a de novo mutation. Only one known case has been detected prior to birth by ultrasound technique. Thus, clinicians must perform thorough physical examinations on newborns and be alert to the dysmorphic and neurological features of this syndrome. The prognosis is dependent on the nature and severity of defects as well as early, consistent medical, dental, and development care for children with this syndrome.
Bibliography
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