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Introduction

Rubinstein–Taybi syndrome (RTS), also known as broad thumb-hallux syndrome or Rubinstein syndrome,[1] is a condition characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes.[2] Other features of the disorder vary among affected individuals. People with this condition have an increased risk of developing noncancerous and cancerous tumors, leukemia, and lymphoma. This condition is sometimes inherited as an autosomal dominant pattern and is uncommon, many times it occurs as a de novo (not inherited) occurrence, it occurs in an estimated 1 in 125,000-300,000 births.

Features of Rubinstein-Taybi Syndrome

Features of Rubinstein-Taybi syndrome include varying levels of intellectual disability, specifically in regards to memory and learning, as well as decreased growth from birth to 6 weeks of age. Physical features of patients with Rubinstein-Taybi syndrome include cardiac abnormalities, such as atrial and ventricular septal defects. These defects are caused by holes in the barriers separating the atria and ventricles respectively. Some of these cardiac abnormalities were diagnosed from birth. Facial abnormalities of the disease include prominent and beaked noses, with the bones separating the nostrils low, arched eyebrows, eye folds, and hair connecting the eyebrows. Patients may have broad fingers sometimes accompanied by additional digits, and underdeveloped nails. The fifth digits of feet and hands may also be broad. Patients show kidney abnormalities, and an increased chance of forming keloids (irregular fibrous tissues formed at the site of a scar). Individuals with Rubinstein-Taybi syndrome are more likely to develop tumours, with leukaemia being common in children and meningioma in adults. Some individuals have been reported to suffer from intestinal malrotation caused by blockages in the digestive system. Other external physical features include short stature as well as smallness of the head.

Patients with Rubinstein-Taybi syndrome also show issues with mental health. Studies suggest individuals with Rubinstein-Taybi syndrome are capable of forming relationships and interacting socially despite their intellectual disabilities. Patients have also shown short attention spans and lack of physical coordination. Mood changes have been reported in patients as they grow through adulthood. The CPB protein is important in the development of individuals, however it is also important in the functioning of adult cognitive ability.

Epigenetics

CREBBP is a gene that encodes for the CREB-binding protein, which activates transcription factors that are necessary for normal human development. CREBBP utilizes methyltransferases and acetyltransferases to regulate gene expression. Mutations within the cytogenetic location 16p13.3 affect the intrinsic histone acetyltransferases of CREBBP, preventing acetylation of histones H3 and H4. This causes a decrease in the expression of genes necessary for the normal development of individuals, which can result in Rubinstein-Taybi syndrome.

The CREB-binding protein is closely related in function to the p300 gene. CREBBP and p300 use acetylation to regulate the tumour suppressor gene p53. Mutations within 22q13.2 affect the p300 gene's ability to regulate p53. Both CBP and p300 are involved in the acetylation of the lysine residues: H4K5, H3K14, H3K18, H3K27 and H3K56. Deletions in exon 22 can cause a loss of CBP acetylation transferase, leading to Rubinstein-Taybi syndrome.

Epidemiology

Rubinstein-Taybi is a rare disease, and is estimated to affect between 1 in 100,000 and 700,000 individuals. A majority of cases are a result of De novo mutations, meaning they are present for the first time in the afflicted individual. Deletions within the cytogenetic location 16p13.3 occur in 50% of patients, whereas deletions within 22q13.2 are less prevalent. There are 92 different possible mutations within histone acetyltransferases, and mutations within CREBBP are located in 41% of patients. Cardiac problems are found in 24-38% of patients, while chromosome rearrangements have been reported to make up 15.5% of patients with the disease. Point mutations are more prevalent and have been found in 84.5% of Rubinstein-Taybi syndrome patients.