Rubinstein - Taybi Syndrome (Rubinstein syndrome, broad thumb-hallux syndrome, broad thumbs and great toes, characteristic facies and mental retardation)
Rubinstein-Taybi Syndrome (Rubinstein syndrome, broad thumb-hallux syndrome, broad thumbs and great toes, characteristic facies and mental retardation) ICD-9 759.89; OMIM #180849
Are You Confident of the Diagnosis?
Characteristic findings on physical examination
Diagnosis is predominantly based on clinical findings:
Musculoskeletal: broad thumbs and toes (99%), some with angulation, short stature, stiff gait, postnatal growth retardation (
Craniofacial: beaked nose with nasal septum extending below the nostrils (87%), broad nasal bridge, downslanting palpebral fissures, hypertelorism, long eyelashes, high-arched palate, epicanthal folds, ’grimacing’ smile, mild micrognathia, microcephaly, prominent nose, malpositioned ears with dysplastic helices, hypoplastic maxilla, head circumference below 50th percentile
Neurologic: mental retardation, speech delay, motor retardation, hypotonia
Dermatologic: capillary malformations in 50%, hirsutism, supernumerary nipples
Ophthalmologic: strabismus, ptosis, cataracts
Broad thumbs with angulation. (Courtesy of Dr. Kenneth Greer)
Expected results of diagnostic studies
X-rays of hands and feet with thumbs pressed flat may show:
Thumbs with delta-shaped proximal phalanges
Short, broad distal phalanx
Small hole/notch in the distal phalanx
Angulation of the distal phalanges
Duplication of the proximal and/or distal phalanges of the great toes
Angulation deformity of the hallux
In genetic testing the detection of an identified mutation will be possible in 50% of patients. Fluorescent in-situ hybridization (FISH) and MLPA (multiplex ligation-dependent probe amplification) are initial tests of choice. CREBBP can be screened for point mutations, small deletions or insertions.
Who is at Risk for Developing this Disease?
The risk of developing this disease is 1 in 100,000-125,000 newborns and up to about 1 in 300 of institutionalized mentally retarded patients.
What is the Cause of the Disease?
About 50% of patients have mutations in one of two genes: CREBBP (cAMP-response-element binding protein) on chromosome 16, which is10 times more common than EP300 mutations and EP300 (EIA Binding Protein P300).
Patients with EP300 mutations may have milder musculoskeletal abnormalities including normal hands and feet.
Though the transmission is autosomal dominant, most cases are de novo mutations.
Both genes encode histone acetyltransferases (HAT), which are involved in numerous signaling pathways.
Systemic Implications and Complications
Patients with Rubinstein-Taybi are at risk for many other medical conditions and complications including:
Gastroesophageal reflux disease
Congenital heart disease in approximately 35% of patients
Reported anomalies include: ventricular and atrial septal defects, patent ductus arteriosus, coarctation of aorta, pulmonic stenosis, aortic stenosis, dextrocardia, conduction problems
Incomplete or delayed descent of testes and hypospadias in males
Talon cusps of secondary dentition, crowded and malpositioned teeth, gingivitis, natal teeth, hypo and hyper-dontia
Higher tendency to form keloids
Increased incidence of pilomatricomas
Possible increased risk of benign and malignant tumors
Possible increased risk of leukemia and lymphoma (Acute lymphocytic leukemia, Non-Hodgkin lymphoma)
Abnormal EEG findings
Possible increased risk of neural tumors (medulloblastoma, neuroblastoma, meningioma)
Possible increased risk of thickened filum terminale, tethering of the spinal cord and spinal lipoma
Congenital or acquired scoliosis, kyphosis and lordosis
Increased risk of fractures
Children with severe angulation of their thumbs can have functional impairment and should be referred for possible surgical repair before age 2
Lacrimal apparatus abnormalities
Short attention span
Motor stereotypies (repetitive movements, arm flapping)
Difficulty with anesthesia due to increased risk of aspiration
Difficulty with intubation due to a relatively anterior larynx and cardiac anomalies
Obstructive Sleep Apnea
Treatment options are obviously very broad and numerous based on the phenotypic variations that are present in patients with this syndrome. A comprehensive approach to treatment involves a multidisciplinary team of medical providers familiar with this syndrome.
Orthopedic evaluation is especially important early in life to correct any defects that may cause functional impairment. For capillary malformations, a pulsed dye laser is often the best treatment option though several treatment sessions may be necessary.
Suggested baseline evaluations:
Electrocardiogram, echocardiogram and pediatric cardiology evaluation
Pediatric ophthalmologic evaluation
Ultrasound of the spine
Developmental pediatrician evaluation
Blood pressure monitoring yearly beginning at age three
Dental exams beginning at age one
Yearly hearing tests and eye exams
Monitoring of weight, height, head circumference and weight-for-height on Rubinstein-Taybi specific growth grids
Referral to an early intervention educational program
Unusual Clinical Scenarios to Consider in Patient Management
Premature thelarche (breast development)
Striate palmoplantar keratoderma
What is the Evidence?
Rubinstein, J. "Broad thumb-hallux (Rubinstein-Taybi) Syndrome 1957-1988". Am J Med Gen Suppl . vol. 6. 1990. pp. 3-16.(An early review of 571 cases, this article provides a detailed description of the physical findings in this syndrome.)
Wiley, S, Swayne, S, Rubinstein, J, Lanphear, N, Stevens, C. "Rubinstein-Taybi syndrome medical guidelines". Am J Med Genet. vol. 119A. 2003. pp. 101-110.(This article includes specific surveillance and intervention recommendations compiled by a group of pediatric experts.)
Cantani, A, Gagliesi, D. "Rubinstein-Taybi syndrome. Review of 732 cases and analysis of typical traits". Eur Rev Med Pharmacol Sci. vol. 2. 1998. pp. 81-87.(This is an analysis of 732 cases and provides a summary of the physical findings of the syndrome and discusses epidemiology and genetics known at the time of publication.)
Roelfsema, J, Peters, D. "Rubinstein-Taybi syndrome: clinical and molecular overview". Expert Rev Mol Med. vol. 9. 2007. pp. 1-15.(This article details the molecular basis of the disease, discussing the role of CREBBP and EP300 in the pathogenesis of Rubinstein-Taybi syndrome.)
van Genderen, M, Kinds, G, Riemslag, F. "Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature". Br J Ophthalmol. vol. 84. 2000. pp. 1177-1184.(This reviews the ophthalmologic findings of 24 selected Dutch Rubinstein-Taybi patients and emphasizes the prevalence of retinal abnormalities. The authors recommend regular visual function tests and electrophysiological studies in these patients.)
Galera, C, Taupiac, E, Fraisse, S, Naudion, S, Toussaint, E, Rooryck-Thambo, C. "Socio-behavioral characteristics of children with Rubinstein-Taybi syndrome". J Autism Dev Disord. vol. 39. 2009. pp. 1252-1260.(This is a case-control study that used caregiver responses on standardized questionaires to detail the behavioral aspects of Rubinstein-Taybi syndrome. The authors concluded that Rubinstein-Taybi patients had specific behaviors including short attention span and poor coordination.)
Miller, R, Rubinstein, J. "Tumors in Rubinstein-Taybi syndrome". Am J Med Genet. vol. 56. 1995. pp. 112-115.(This is a summary of the tumors reported in Rubinstein-Taybi patients up to the date of publication and the authors emphasize that there is a pattern of neural and developmental tumors present in these patients.)
Kurosawa, K, Masuno, M, Imaizumi, K, Matsuo, M, Kuroki, Y, Tachibana, K. "Premature thelarche in Rubinstein-Taybi syndrome". Am J Med Genet . vol. 109. 2002. pp. 72-73.(This letter to the editor describes several reports of premature thelarche in girls with Rubinstein-Taybi syndrome.)
Naimi, DR, Munoz, J, Rubinstein, J, Hostoffer, RW. "Rubinstein-Taybi syndrome: an immune deficiency as a cause of recurrent infections". Allergy Asthma Proc . vol. 27. 2006. pp. 281-284.(This article describes 3 patients with increased respiratory infections and a defect in antibody-response.)
Nakai, K, Yoneda, K, Moriue, T, Kubota, Y. "Striate palmoplantar keratoderma in a patient with Rubinstein-Taybi syndrome". Eur Acad Dermatol Venereol. vol. 23. 2009. pp. 333-5.(This is a case report of a Japanese patient with a clinical diagnosis of Rubinstein-Taybi syndrome and a striate palmoplantar keratoderma in which the authors postulate that a mutation of the cyclic AMP-response element binding protein may cause an abnormal expression of involucrin.)
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