Rubinstein-Taybi Syndrome

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860 In 1963, Rubinstein and Taybi described a new syndrome characterized by broad thumbs and toes, facial abnormalities, and mental retardation. The prevalence of Rubinstein-Taybi syndrome is estimated to be 1 in 100,000 to 125,000 live births in the Netherlands.

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal dominant

2. Caused by deletions or heteroallelic mutations of CREBBP, the gene for cAMP responsive element binding (CREB) protein, which resides on chromosome 16p13.3. CREBBP is a large nuclear protein involved in transcription regula- tion, chromatin remodeling, and the integration of several different signal transduction pathways. The following muta- tions of CREBBP were reported in patients with Rubinstein- Taybi syndrome:

a. Chromosomal translocations/inversions

b. Deletions at the microscopic and submicroscopic level

c. Molecular mutations

3. Mutations in the CREBBP gene are responsible for:

a. Rubinstein-Taybi syndrome

b. t(8;16)-associated acute myeloid leukemia

4. No clear phenotypic differences observed between patients in which microdeletions or truncating mutations were found

CLINICAL FEATURES

1. Characteristic craniofacial features a. Microcephaly (35–94%) b. Prominent forehead

c. Down-slanting palpebral fissures d. Apparent ocular hypertelorism e. High-arched or heavy eyebrows

f. Long eyelashes g. Epicanthal folds

h. Prominent nose with columella (lower margin of the nasal septum) below the alae nasi

i. Malpositioned ears with dysplastic helices j. Grimacing smile

k. Hypoplastic maxilla l. Mild retrognathia m. High arched palate 2. Skeletal abnormalities

a. Thumbs

i. Broad terminal phalanges

ii. Severe radial angulation deformity (“hitch-hiker thumbs”) with abnormal shape of proximal pha- lanx, which prevents opposition and functional gripping strength

b. Great toes

i. Broad terminal phalanges

ii. Angulation deformity with abnormal shape of proximal phalanx or first metatarsal

iii. Duplicated proximal phalanx iv. Duplicated distal phalanx c. Short stature (78%)

d. 5th finger clinodactyly e. Overlapping toes

f. Broad terminal phalanges of other fingers g. Pelvic anomalies

i. Flat acetabular angles ii. Flaring of the ilia iii. Notch in the ischia h. Stiff gait

i. Lax ligaments j. Hyperextensible joints k. Vertebral anomalies

i. Spina bifida ii. Kyphosis iii. Lordosis

iv. Scoliosis

l. Sternal or rib anomalies i. Premature fusion ii. Simian sternum

iii. Pectus excavatum or carinatum iv. Forked ribs

v. Cervical ribs

vi. Fusion of the first and second ribs 3. History of maternal polyhydramnios (39%) 4. Hypotonia

5. Developmental delay 6. Variable mental retardation

a. Severe in some patients

b. Moderate degree in many patients c. Mild in some patients

7. Behavioral/psychiatric disorders a. Childhood

i. Short attention span ii. Impulsiveness

iii. Clinically nonsignificant stereotype iv. Withdrawal

v. Nonspecific ‘maladaptive behavior’

vi. Repetitive motions vii. Resistance to change viii. Distractibility

ix. Aggressive outbursts x. Difficulty in sleeping b. Adulthood

i. Mood disorders

ii. Chronic motor tic disorder iii. Obsessive compulsive disorder

iv. Depressive disorder

v. Bipolar disorder

vi. Tourette disorder

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vii. Trichotillomania

viii. Pervasive developmental disorder ix. Self-injurious behaviors

x. Autistic features 8. Seizures (27–28%) 9. Ophthalmologic problems

a. Strabismus (60–71%) with subsequent risk of amblyopia

b. Refractive errors (41–56%)

c. Lacrimal duct obstructions (38–47%) d. Ptosis (29–32%)

e. Coloboma (9–11%)

f. Duane retraction syndrome (8%) g. Ghost vessels

h. Peters anomaly i. Optic nerve hypoplasia j. Cataracts

k. Corneal opacities l. Congenital glaucoma m. Retinal abnormalities 10. Dental manifestations (67%)

a. Talon cusps of secondary dentition b. Crowding and malpositioned teeth

c. Anterior and posterior crossbites secondary to a narrow palate or jaw size discrepancy

d. Natal teeth e. Gingivitis

f. Hypo/hyperdontia g. Increased rate of carries

11. Upper airway obstruction during sleep due to:

a. Hypotonia

b. Anatomy of the oropharynx and airway i. Small nasal passages

ii. Retrognathia iii. Micrognathia

iv. Hypertrophy of the tonsils and adenoids v. Obesity

12. Gastrointestinal problems

a. Significant gastroesophageal reflux b. Feeding difficulties

c. Constipation

13. Congenital heart disease (24–38%) a. ASD

b. VSD c. PDA

d. Coarctation of the aorta e. Pulmonary stenosis

f. Bicuspid aortic valve g. Pseudotruncus h. Aortic stenosis

i. Hypoplastic left heart syndrome j. Complex congenital heart defects k. Dextrocardia

l. Vascular rings m. Conduction problems 14. Renal anomalies (52%)

a. Hydronephrosis b. Duplications c. Vesicoureteral reflux d. Urinary tract infections

e. Renal stones f. Nephrotic syndrome g. Neurogenic bladder 15. Cutaneous manifestations

a. Tendency of keloid and hypertrophic scar formation b. Ingrown toenails

c. Toenail paronychia (44%) d. Fingernail paronychia (9%) e. Pilomatrixomas

f. Capillary hemangioma i. Forehead

ii. Nape of the neck iii. Back

g. Supernumerary nipples h. Hirsutism

i. Transverse palmar creases

j. Deep plantar crease between the first and second toes 16. Orthopedic problems

a. Hypotonia b. Lax ligaments c. Tight heel cords d. Elbow abnormalities e. Legg-Perthes disease (3%)

f. Dislocated patella (2.5%) g. Congenital hip dislocation (1.4%) h. Slipped capital femoral epiphysis (0.6%)

i. Congenital or acquired scoliosis, kyphosis, and lordosis j. An increased risk of associated thickened filum termi-

nale, tethering of the cord, and lipoma k. An increased risk of fractures

17. An increased risk of having benign and malignant tumors as well as leukemia and lymphoma

a. Oligodendroglioma b. Medulloblastoma c. Neuroblastoma d. Meningioma e. Pheochromocytoma

f. Nasopharyngeal rhabdomyosarcoma g. Leiomyosarcoma

h. Seminoma

i. Embryonal carcinoma j. Odontoma

k. Choristoma l. Dermoid cyst m. Pilomatrixomas

DIAGNOSTIC INVESTIGATIONS

1. Developmental evaluation

2. Echocardiography for cardiac defects 3. Ophthalmologic examination 4. Renal ultrasound

5. Voiding cystourethrogram 6. Hearing evaluation 7. EEG abnormalities 8. Radiography

a. Hands

i. Broad 1st distal phalanx ii. Broad 1st ray

iii. Duplicated 1st distal phalanx

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iv. Delta-shaped proximal phalanges of the thumbs v. Mushroom-shaped distal phalanges

vi. Angulation of the distal phalanges vii. Thin tubular bones

viii. Delayed bone age (74%) b. Feet

i. Broad 1st distal phalanx ii. Broad 1st ray

iii. Duplicated 1st distal phalanx

iv. Duplicated 1st proximal and distal phalanx v. Delta-shaped 1st proximal phalanx. A duplicated

longitudinal bracketed epiphysis (“kissing delta”

phalanx) always involve the proximal phalanx of the great toe

vi. Angulation deformity of the hallux vii. Mushroom-shaped distal phalanges viii. Very small distal phalanges

ix. Thin tubular bones x. Protruding calcaneus

xi. Synostosis of cuneiform ossicles xii. Proximally split 5th metatarsal bone c. Limbs

i. Thin tubular bones ii. Fractures

iii. Patella luxations d. Spine

i. Cervical hyperkyphosis ii. Lumbar hyperlordosis iii. Scoliosis

iv. Spina bifida occulta: cervical or lumbosacral v. Spondylolisthesis

vi. Irregular thoracic endplates e. Skull

i. Microcephaly ii. Absent sinus frontalis iii. Deviated nasal septum

iv. Steep skull base

v. Abnormally-shaped sella turcica vi. Foramina parietale permagna vii. Prominent digital marking f. Thorax

i. Narrow thoracic aperture ii. 11 ribs

iii. Fusion of ribs iv. High diaphragm g. Pelvis

i. Small iliac wings ii. Flaring iliac wings

iii. Irregularly formed acetabulum iv. Symphysiolysis

9. Diagnosis of Rubinstein-Taybi syndrome a. Made primarily by clinical examination b. Confirmed by the presence of microdeletion 10. Cytogenetic analysis

a. FISH analysis with cosmids from the CBP region to detect chromosome 16p13.3

b. Chromosome abnormalities i. t(2;16)(p13.3;p13.3) ii. t(7;16)(q34;p13.3) iii. Inv(16)(p13.3q13)

11. Mutation analysis of CREBBP gene a. SSCP

b. Genomic sequencing

c. Protein truncation test (10% of cases)

d. Fluorescent in situ hybridization (FISH) probes i. Specific for chromosome region 16p13.3 ii. Containing regions of the cyclic AMP-respon-

sive element-binding protein gene (CBP gene) iii. Microdeletions identified in approximately 10%

of patients by five cosmid probes containing almost the entire gene

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: 0.1% based on empiric data

b. Patient’s offspring: as high as 50%, particularly in individuals with deletions

2. Prenatal diagnosis: possible for fetuses at risk using FISH on fetal cells obtained by amniocentesis or chorionic vil- lus sampling, provided the FISH has identified a deletion in an affected family member

3. Management

a. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy

b. Management of gastroesophageal reflux

c. Prophylaxis for subacute bacterial endocarditis for patients at risk

d. Require assistance and training in self-help skills but can become self-sufficient in most self-help areas such as feeding, dressing, and toileting

e. Special education f. Behavioral modification

g. Surgery to correct a delta phalanx deformity h. Caution with general anesthesia in children

i. Challenging to intubate due to airway anomalies a) Relatively anterior position of the larynx b) Easily collapsible laryngeal wall

ii. Important to intubate due to the high risk of aspi- ration during induction and emergence

iii. Presence of skeletal anomalies

iv. Cardiac arrhythmia may result from use of car- dioactive drugs

a) Atropine b) Neostigmine c) Succinylcholine d) Suxamethonium

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Fig. 1. A patient with Rubinstein-Taybi syndrome at different ages (childhood and adulthood) showing typical facial appearance (prominent beaked nose with the columella below the alae nasi), broad thumbs, and broad/bifid great toes, which are illustrated by radiographs.

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Fig. 2. An adult with Rubinstein-Taybi syndrome showing the charac- teristic facies and broad thumbs.

Fig. 3. A young patient with Rubinstein-Taybi syndrome showing characteristic facies, broad thumbs, and great toes.