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 (Figure 1)

  • 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

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  • Neurologic: mental retardation, speech delay, motor retardation, hypotonia

  • Dermatologic: capillary malformations in 50%, hirsutism, supernumerary nipples

  • Ophthalmologic: strabismus, ptosis, cataracts

Figure 1.

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?
Etiology

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.

Pathophysiology

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:

Gastrointestinal

  • Gastroesophageal reflux disease

  • Feeding difficulties

  • Constipation

Cardiac

  • 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

  • Hypertension

Genitourinary

  • Renal anomalies

  • Incomplete or delayed descent of testes and hypospadias in males

Dental Problems

  • Talon cusps of secondary dentition, crowded and malpositioned teeth, gingivitis, natal teeth, hypo and hyper-dontia

Dermatologic

  • Higher tendency to form keloids

  • Increased incidence of pilomatricomas

Hematologic/Oncologic

  • Possible increased risk of benign and malignant tumors

  • Possible increased risk of leukemia and lymphoma (Acute lymphocytic leukemia, Non-Hodgkin lymphoma)

Neurologic

  • Seizures

  • 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

Orthopedic

  • 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

Ophthalmologic

  • Retinal dysfunction

  • Lacrimal apparatus abnormalities

  • Corneal abnormalities

  • Glaucoma

  • Refractive errors

  • Colobomata

Socio-Behavioral/Developmental

  • Short attention span

  • Motor stereotypies (repetitive movements, arm flapping)

  • Poor coordination

  • Obesity

Other

  • 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

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.

Patient Management

Suggested baseline evaluations:

  • Electrocardiogram, echocardiogram and pediatric cardiology evaluation

  • Pediatric ophthalmologic evaluation

  • Renal ultrasound

  • Ultrasound of the spine

  • Hearing evaluation

  • Developmental pediatrician evaluation

Further Monitoring:

  • 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)

  • Immunodeficiency

  • 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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