Adress correspondance to : Dominique Thomas, MD, Dept of Obstetrics and Gynecology, Hôpital Iris Sud, sîte Ixelles, 63 rue J. Paquot 1050 Bruxelles Belgium, tel: 32 2 641 85 35 Fax: 32 2 641 85 36

Synonyms: Rubinstein-Taybi syndrome

Definition: Multiple congenital anomaly syndrome comprising mental retardation, broad thumbs and halluces, great toes, typical facial appearance, short stature¹.

Case report:

A 26-year-old G2P1 patient was referred for infertility. An endometriosis stage IV was diagnosed by laparoscopy. She was treated by intra-muscular injection of superactive analog of LHRH. She became pregnant after the third injection.

When she underwent routine ultrasound at 12^th weeks, an abnormal sonolucency of the neck (6 mm) was noticed without any other structural abnormalities. A trans-cervical chorionic villus sampling revealed a normal 46 XX chromosome pattern.

Follow-up ultrasound was performed at 21, 31, 32, 33 and 34 weeks, and the following features were found:

• Shortening of all long bones (humerus, radius, ulna, femur, tibia, fibula). The measurements were under the 5^th percentile at 21 weeks and after, but the growth was parallel to normal curves (fig: femur: 51 mm, 32 weeks), with femur/foot ratio: 0.8.

• An abnormal profile with retrognathism.(fig, fetal profile 32 weeks)

• Mild right pyelectasy (7.5mm) (fig. abdominal cross- section, 31 weeks) with abnormal hyperechoic kidney cortex suggesting a right renal dysplasia

• An abnormal left kidney, which appeared very long and unusual in shape with abnormal cortico-medullar differentiation (fig.).

• The bladder was full during all the examinations, so we suspected an abnormality of micturition. (fig. full bladder 34 weeks).

• an enlarged umbilical portion of portal vein

• The most important finding that pointed to the diagnosis was the abnormal angulation between thumb and radius (fig.: forearm and thumb lateral view 34^th weeks).

• growth retardation was present after 31 weeks (abdominal and head perimeter below the 10^th percentile)

• Moderate hydramnios (amniotic fluid index >95^th percentile)
  

The patient was followed to term. An amniocentesis at 32 weeks confirmed the earlier diagnosis of normal karyotype.
Spontaneous delivery occurred at 35 weeks. The birth weight was 2040 grams, size:41 cm, HC 28.5 cm.
Post-natal evaluation confirmed facial dysmorphology and abnormality of hands with broad thumbs and radial angulation

Post-natal evaluation confirmed facial dysmorphy and abnormality of hands with broad thumbs and radial angulation ( fig 8).

The diagnosis of Rubinstein-Taybi syndrome was finally made by identification of the abnormality on 16p13.3 by fluorescence in-situ hybridization (FISH) on the cultured amniotic cells (fig 8).

History:

In 1963 Rubinstein and Taybi described seven children with a new recognizable syndrome². Coffin, the following year, reported six further cases and proposed the eponymous title³. Since the initial description, additional publications related to Rubinstein-Taybi syndrome gave new data on the natural history of the syndrome and especially the change in facial appearance in individuals affected⁴ and the presence of associated cardiac abnormalities of potential severity in 32.6% of affected patients.

Details of natural history were given by many authors and are the following:

• Average duration of pregnancy and average growth parameters are normal at birth. 39% of pregnancies are complicated by polyhydramnios.
• 20% of neonates are admitted in neonatal intensive care unit with an average stay of 14 days, with medical problems as respiratory difficulties (38%), apnea (24%), feeding problems (88%) severe constipation (74%)⁶, swallowing difficulties with easy choking⁷.
• The face of newborn infant is characteristic with upward slanting palpebral fissures, abundant dark scalp hair, facial hirsutism and puffy appearance, relatively prominent forehead, straight nose with short upturned tip, normal or long philtrum and small chin⁷. The mouth is small and micrognathia or retrognathia is almost universal⁴. Cleft palate, cleft upper lip can be part of the syndrome⁸. The facial aspect change during the life and the nose take the “Cyrano-type” appearance⁴
• 16% of patients have myopia¹ and other ocular abnormalities.
• Dental abnormalities are frequent and 92% of the subjects have talon cups in all permanent dentition, which is a clue to the diagnosis.
• The growth in Rubinstein-Taybi syndrome is abnormal, because height, weight and OFC fall below 5^th percentile the first few month of the life⁹.
• There is frequently a generalized delay of skeletal maturation. There is a high incidence of fractures, but it is not demonstrated that it is due to slender of long bones⁷. 100% of patients have small hands with broad distal phalanges of thumbs and fingers, and 22% have radially deviated thumb⁷. Halluces are broad or partially duplicated⁷.
• Mental retardation is present, 74% of subjects have IQ under 50¹. Other neurological problems are: hypotonia, and a stiff awkward gait and seizures.
• Congenital heart defect are seen in 32.6% of patients⁵. The most common defects are patent ductus arteriosus, ventricular septal defect atrial-septal defect and coarctation of the aorta.
• Structural and functional urinary tract problems are noticed in 28% of affected patients⁶, with one case of decreased bladder tone.
• Cutaneous findings include unusual dermatoglyphic patterns and keloïds¹.
• Abnormalities of glucose metabolism and neoplasms have been described^1,11.

Prevalence:

The reported incidence of Rubinstein Taybi Syndrome is 0.01:10.000 live births, and 1/300 institutionalized subjects¹².

Etiology:

Most cases are sporadic. The disorder has been located to 16p13.3 and then permits subsequent identification of submicroscopic deletion of this region¹³.

Pathogenesis:

16p13.3 is the region encompassing the 3’ end of cyclic AMP responsible binding protein gene. This protein is ubiquitously expressed as a coactivator in cyclic AMP regulated gene expression¹⁴, what explains the multisystem problems encountered by patients with non specific features.

Sonographic findings:

No previous prenatal description of Rubinstein-Taybi syndrome` has been reported to our knowledge.

Prenatal features suggest a skeletal dysplasia. In this setting, the findings are:

• Short limbs are seen (generalized micromelia) without abnormality of spine nor ribs and thorax. There is neither bone deformity nor poor or absent mineralization. This aspect is confirmed by femur/ foot length ratio under the fifth percentile at 32th weeks. However postnatal studies describe retarded osseous maturation and short stature later in the life but not neonatal limb shortening. We consider in this case that delayed osseous maturation begin during intra-uterine life.
• An abnormal profile with retrognathism.
• The clue to diagnosis is achieved by the appearance of the radial deviation of the thumb. It could be more clearly seen by tri-dimentional echography and probably the broad thumb too. The radial angulation is caused by the proximal phalange, which has a trapezoid delta shape¹.

The other non-skeletal features are:

• An abnormal nuchal translucency. It is well known that it is a good marker of genetic syndrome, structural anomaly and single gene disorder : 23,2% of normal karyotype fetuses with increased nuchal translucency¹⁵.
• An increased amniotic fluid volume probably due to abnormal fetal swallowing.
• A dysplastic aspect of right kidney with no emptying of the bladder.
• An abnormality of umbilical vein in portal portion without heart abnormality

Differential diagnosis:

• Hitchhiker thumb: Apert syndrome, diastrophic dysplasia, Pfeiffer syndrome, chromosome 13 trisomy.
• Very small stature: De Lange syndrome, Russell-Silver syndrome, Mulibrey nanism syndrome, Dubowitz syndrome, Bloom syndrome, De Sanctis- Cchione syndrome, Johanson-Blizzard syndrome, Seckel Syndrome, Hallermann- Streiff syndrome, Smith-Lemli-Opitz syndrome, Williams syndrome, Noonan syndrome, Aarskog syndrome, Robinow syndrome, Opitz syndrome, Opitz-Frias syndrome, Saethre-Chotzen Syndrome.

Prognosis:

The psychosocial prognosis is quite poor because of low IQ and a significant morbidity due to associated congenital heart defects.

Recurrence risk:

Autosomal dominant disorder.

The recurrence risk for offspring of affected individuals is 50%

The empiric recurrence risk for sibs is 0.1% (16).

Management:

If the diagnosis is made by FISH on cultured amniocytes , with the experience of Petrij et al¹⁷, we can expect to detect 10.8% of affected babies with the use of 5 cosmid probes. Before legal limit for termination of pregnancy, this option may be offered to the parents.

References:

1.    Rubinstein JH. Broad Thumb-Hallux (Rubinstein- Taybi) Syndrome 1957-1988. Am. J Med Genet (Suppl)1990; 6:3-16.

2.     Rubinstein JH, Taybi H. Broad Thumbs and toes and facial abnormalities: a possible mental retardation syndrome: A possible mental retardation sydrome. Am J Dis Child 1963; 105: 588-608.

3.    Coffin GS. Brachydactyly, peculiar facies and mental retardation. Am J Dis Child 1964; 108 : 351-359.

4.    Allanson J. Rubinstein- Taybi syndrome: the changing face. Am J Med Genet (Suppl) 1990; 6: 38-41.

5.    Stevens C, Bhakta M. Cardiac Abnormalities in the Rubinstein- Taybi Syndrome. Am J Med Genet 1995; 59: 334-348.

6.    Stevens C, Carey J, Blackburn B. Rubinstein- Taybi Syndrome: A natural history study. Am J Med Genet ( Suppl) 1990; 6:30-37.

7.    Hennekam R, Van den Boogaard MJ, Sibbles B, Van Spijker H. Rubinstein Taybi Syndrome in the Nederlands. Am J Med Genet (Suppl) 1990; 6: 17-29.

8.    Henekam R, Van Doorne J. Oral aspects of Rubinstein-Taybi Syndrome. Am J Genet ( Suppl) 1990; 6: 17-29.

9.    Stevens C, Hennekam R, Blackburn B. Growth in the Rubinstein-Taybi Syndrome. Am J Med Genet (Suppl) 1990; 6: 51-55.

10.  Hennekam R, Van den Boogaard MJ, Dijkska P, Van de Kamp J. Metacarpophalangeal Pattern profile analysis in Rubinstein- Taybi Syndrome. Am J Genet (Suppl) 1990; 6:48-50.

11.  Bilir R, Bilir N, Wilson G. Intracranial Angioblastic meningioma and an aged appearance in a woman with Rubinstein- Taybi Syndrome. Am J Genet (Suppl) 1990; 6: 69-72.

12.  Bery C., Rubinstein-Taybi Syndrome. J Med Genet 1987; 24: 562-566.

13.  Lacombe D, SauraR, Taine L, Battin J. Confirmation of assignment of a locus for Rubinstein-Taybi syndrome gene to 16p13.3. Am J Med Genet 1992; 44: 126-128.

14.  Chen X, Korenberg J. Localization of human CREBBP (CREB binding protein ) to 16p13.3 by fluorescent in situ hybridization. Cytogenet Cell Genet 1995; 71: 56-57.

15.  Bilardo C, Pajkrt E, De Graaf I, Mol B, Bleker O, Outcome of fetuses with enlarged nuchaltranslucency and normal karyotype. Ultrasound Obstet. Gynecol. 1998; 11: 401-406.

16.  Hennekam R, Stevens C, Van de Kamp J. Etiology and Recurrence Risk in Rubinstein-Taybi Syndrome. Am J Med Genet (Suppl) 1990 6: 56-64.

17.  Petrij F, Dauwerse H, Blough R, Giles R, Van der Smagt J, Wallerstein R, Maaswinkel-Mooy P, Van Karnebeek C, Van Ommen, Van Haeringen A, Rubinstein J, Saal H, Hennekam R, Peters D, Breuning M. Diagnostic analysis of Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J. Med Genet 2000; 37: 168-176.