syndrome of the monthfamily in which an apparently affected mother had two affected children and...

Syndrome of the month

Journal of Medical Genetics 1987, 24, 562-566

Rubinstein-Taybi syndromeA CAROLINE BERRYFrom the S E Regional Genetics Centre, Guy's Hospital, London SE] 9RT.

In 1963 Rubinstein and Taybi' described sevenchildren with mental handicap, broad thumbs andbig toes, and very similar faces. They believed thisto be a new and recognisable syndrome. Thefollowing year Coffin2 confirmed this view, report-ing six further cases, and it was he that proposed theeponymous title.

Epidemiology

This is a rare cause of mental handicap. Case findingstudies in several English speaking countries havefound about one case per 300 institutionalisedsubjects.3 Assuming that at that time about 1 per1000 of the general population required institutiona-lisation the population frequency would be about 1in 300 000. Sex ratio, j3arental ages, pregnancyhistory, and birth weights have been unremarkablein all studies. Cases have been reported from allracial groups.45

Clinical features' 2 4 6 7

Mental handicap or developmental delay is univer-sally present with IQ estimations ranging from 20 to80. The mean in those diagnosed young is probablyaround 50 though in two reported adult series, allinstitutionalised, the mean was 36 in one6 and 27 inthe other.8

Stature is generally below the 25th centile, withthe majority falling below the 3rd centile. Headcircumference is also usually below the 3rd centilebut may reach the 25th. In infancy the anteriorfontanelle may be unusually large.The following facial features are diagnostically

important (figs 1 and 2).

EYESAntimongoloid slant to palpebral fissures secondaryto maxillary hypoplasia, long eyelashes, arched

Received for publication 23 March 1987.Accepted for publicattion 24 March 1987.

eyebrows, and epicanthus. Ptosis, myopia, exo-tropia, coloboma, strabismus, and cataracts havealso been reported.

NOSEClassically the nose has a beaked or pinchedappearance. The columella is long and protrudesbeyond the alae nasi. The septum may be deviated.The bridge is often broad and flat.

MOUTHThe palate is usually high arched.

FIG 1 Facial features of child aged nine months.562

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Rubinstein-Taybi syndrome

FIG 2 Facial features of child aged 12 years.

EARS ASSOCIATED FEATURES

The helices are frequently thickened or otherwise Frequent respiratory infections in infancy,' 'doubleunusual and the ear may be low set or malrotated. rows of teeth,9 hirsutism,6 naevus flammeus,'27

and keloid scar formation' 9 have been mentionedAbnormalities of the hands and feet are essentialdiagnostic features, in particular the shape ofthumbs and big toes.

HANDSThe thumbs are disproportionately broad, especiallythe distal phalanx, which may be spatulate. Thefingers, especially the distal phalanges may also bebroad. Clinodactyly of the fifth finger and singlepalmar creases are less specific features. Syndactylyand polydactyly also occur (figs 3 and 4).

FEETThe big toe is usually large and broad. Adultsfrequently show hallux valgus and paronychia (fig5).

OTHER SYSTEMSGenitalia. Undescended testes are common in malesand angulated penis is also reported.Locomotor. Joint laxity is frequent and brisk reflexeshave been observed in a number of cases. Thesefeatures together with the skeletal anomaliesdescribed below are likely to account for thecharacteristic stiff, awkward gait, with flat feet, andslight hip and knee flexion. FIG 3 Hand ofnine month old child.

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FIG 4 Hands-of child of 12 years.

in several case reports and are probably significantassociations. Two (possibly three) cases of acutelymphatic leukaemia have been described in affectedchildren.1'( Several series include children with mildrenal anomalies7 and patent ductus arteriosus.7X ray findings' 3 6 11

A number of abnormalities have been consistentlyreported and are reviewed by Robson et al. 1 lGeneralised delay ofskeletal maturation is frequentlypresent. The foramen magnum is often large and

abnormalities of the cervical spine are common. Inone case cervical spondylolisthesis led to tetra-plegia."1 Fusion of the first and second ribs andsternal abnormalities may be present.X rays in the hands and feet show short, broad,

often irregular terminal phalanges of the thumb andhallux, sometimes with angulation in the thumb (fig6). Duplication of these terminal phalanges has alsobeen described. Less common, but probably signi-ficant, are reports of dislocation of the radial headand patella.9

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FIG 5 Feet of 12 year old child.

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Rubinstein-Taybi syndrome

FIG 6 X ray ofhand at 14 months (bone age nine months).

Differential diagnosis

As with other syndromes in which diagnosis dependsentirely on the clinical features, this is not alwayseasy. The facies is sometimes reminiscent of thatseen in Treacher-Collins syndrome or occasionallySeckel or Hallermann-Streiff syndromes. Broaden-ing of the thumb and big toe may be judgedsubjectively when the facies are suggestive. Also,broad thumbs may occur independently in a men-

tally handicapped person, either as part of normalvariation or as dominantly inherited brachydactylytype D. Both facial and acral features should bepresent for a secure diagnosis.

Aetiology and genetics

Chromosome studies have been essentially normal.One preliminary report'2 suggested that an inter-stitial deletion of chromosome 15, similar to thatseen in Prader-Willi syndrome, might be present,but this was recognised to be an artefact and thesuggestion withdrawn.'3

Consanguinity (father-daughter incest) waspresent in one of the cases of Padfield et a16 and DerKaloustian et all4 have described a first cousinmarriage that gave rise to two affected children.

These children, however, did not have broadthumbs and toes, so their diagnosis must remain indoubt.Other family studies have failed to confirm the

suggestion of autosomal recessive inheritance.Simpson and Brissenden, studying 112 families,found two affected among 243 sibs. This is consider-ably higher than expected from the populationfrequency but quite incompatible with autosomalrecessive inheritance.

Gillies and Roussounis'5 described a pair ofaffected sibs and a second family in which theyproposed the operation of a dominant gene withvariable expression. In this family there were fivesibs, one male being mentally handicapped. He hada sister with a similarly affected son and a brotherwith three children including a son, who showeddevelopmental delay of varying degree. Facialfeatures are said to be similar but not all had broadthumbs, so the authors suggested that insistence onthis feature for diagnosis may result in under-reporting of multiplex families. However, the faceof the proband is not entirely typical and thesuggestion of dominant inheritance here seems farfetched.More recently Cotsirilos et al16 have suggested

autosomal dominant inheritance for a 'syndromesimilar to Rubinstein-Taybi'. They described afamily in which an apparently affected mother hadtwo affected children and four affected sisters. Thetwo children and the five adults all had broadthumbs and big toes but the illustrations of themother's thumbs would be quite compatible withdominantly inherited stub thumbs or brachydactylytype D. She was of normal intelligence as were herfour broad thumbed sisters. The older child hadfacial features compatible with Rubinstein-Taybisyndrome, delayed bone age, brisk reflexes, andmild mental handicap so the diagnosis seems appro-priate for him. The younger sib was only eight weeksold and the facial features, though suggestive, werenot classical. The mother's facial features similarlyshowed the appropriate nose shape but not the othercharacteristic features. The authors suggested thatall seven broad thumbed family members wereaffected despite only one being mentally handi-capped. They invoked variable expression of anautosomal dominant gene to explain this. A morelikely explanation is that there was one truly affectedsubject in a family in which broad thumbs weresegregating in an autosomal dominant manner.The case for autosomal dominant inheritance

seems as yet unproven. Since no subject showing allthe classical hallmarks of the syndrome has repro-duced, there remains the possibility of the full blownsyndrome arising from a dominant mutation.

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Twin studies are of great interest as six concor-dant and four discordant monozygotic pairs havebeen reported.5 1&18 Zygosity has been well estab-lished in the majority of these pairs. The figurespreclude standard single gene aetiology and yet thefrequency of concordance suggests that the causalfactor was present at the time of conception or atleast before the twinning event. An as yet sub-microscopic chromosome deletion could be theresponsible factor, with twins being discordantwhere the event occurred at, or immediately after,the blastocyst splitting. By analogy with Prader-Willi syndrome very occasional families would carrybalanced rearrangements and have more than oneaffected child.An alternative suggestion made by Schinzel et al17

is that the syndrome could arise from an early defectin morphogenesis which might even be causallyrelated to the twinning process.

This discussion has presupposed that the syn-drome is a single homogeneous entity. It is possiblethat a proportion of cases arise from dominantmutations while the remainder are phenocopiesarising after conception. The most attractive andunifying hypothesis is that of a chromosome micro-deletion. The twin and family data, as well as thevariation in the severity of mental handicap and inthe expression of physical features, are all entirelycompatible with this mechanism. Time will tellwhether or not it is the correct one.

Conclusion

Although at present the aetiology of this syndromeremains unknown, the family studies mentionedabove3 show that the risk of recurrence in sibs islow. A figure of 1% seems appropriate for geneticcounselling purposes.

Dr M Baraitser kindly supplied the photographs forfigs 1 and 3.

References

' Rubinstein JR, Taybi H. Broad thumbs and toes and facialabnormalities. Am J Dis Child 1963;105:588-608.

2 Coffin GS. Brachydactyly, peculiar facies and mental retarda-tion. Am J Dis Child 1964;108:351-9.

3 Simpson NE, Brissenden JE. The Rubinstein-Taybi syndrome:familial and dermatoglyphic data. Am J Hum Genet 1973;25:225-9.

4 Filippi G. The Rubinstein-Taybi syndrome. Report of 7 cases.Clin Genet 1972;3:303-18.

5 Kajii T, Hagiwara K, Tsukahara M, Nakajima H, Fukuda Y.Monozygotic twins discordant for Rubinstein-Taybi syndrome.J Med Genet 1981;18:312-4.

6 Padfield CJ, Partington MW, Simpson NE. The Rubinstein-Taybi syndrome. Arch Dis Child 1968;43:94-101.

7 Johnson CF. Broad thumbs and broad great toes with facialabnormalities and mental retardation. J Pediatr 1966;68:942-51.

8 Berg JM, Smith GF, Ridler MA, Dutton G, Green EA,Richards BW. On the association of broad thumbs and first toeswith other physical peculiarities and mental retardation. J MentDefic Res 1966;10:204-20.

9 Rohlfing B, Lewis K, Singleton EB. Rubinstein-Taybi syn-drome. Report of an unusual case. Am J Dis Child 1971;121:71-4.Jonas DM, Heilbron DC, Albin AR. Rubinstein-Taybisyndrome and acute leukaemia. J Pediatr 1978;92:851-2.Robson MJ, Sharrard WJW, Brown LM. Cervical spondylolis-thesis and other skeletal abnormalities in Rubinstein-Taybisyndrome. J Bone Joint Surg (Br) 1980;63:297-9.

12 Wulfsberg EH, Klisak IJ, Sparkes RS. Chromosome 15qdeletion in the Rubinstein-Taybi syndrome. Am J Hum Genet1981 ;33: 127A.

13 Wulfsberg EH, Klisak IJ, Sparkes RS. High resolution chromo-some banding in the Rubinstein-Taybi syndrome. Clin Genet1983;23:35-7.

14 Der Kaloustian VM, Affi AK, Sinno AA, Mire J. TheRubinstein-Taybi syndrome. A clinical and muscle electronmicroscopic study. Am J Dis Child 1972;124:897-902.

15 Gillies DRN, Roussounis SH. Rubinstein-Taybi syndrome.Further evidence of a genetic aetiology. Dev Med Child Neurol1985;27:751-5.

16 Cotsirilos P, Taylor JEC, Matalon R. Dominant inheritance ofsyndrome similar to Rubinstein-Taybi. Am J Med Genet1987;26:85-93.

7 Schinzel AAGL, Smith DW, Miller JR. Monozygotic twinningand structural defects. J Pediatr 1979;95:921-30.

8 Baraitser M, Preece MA. The Rubinstein-Taybi syndrome:occurrence in two sets of identical twins. Clin Genet 1983;23:318-20.

Correspondence and requests for reprints to Dr A CBerry, S E Thames Regional Genetics Centre,Prince Philip Laboratories, Guy's Hospital, LondonSE1 9RT.

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